NOTE: This spoiler was sent in by Sydney.
The film starts out with Willie Dixon (Cedric the Entertainer) narrating. He reflects back to 1941 and focuses on Leonard Chess (Adrien Brody) in Chicago and McKinley Morganfield/Muddy Waters (Jeffrey Wright), a sharecropper in Mississippi.
In Chicago, Leonard wants to marry his girlfriend, Shirley Feder (Jill Flint), but he's in the junk business and therefore doesn't have much money, though he says he's planning to open a club. Unfortunately, Shirley's father disapproves of the match. He says he and Leonard's father came from the same "shithole in Poland" and he didn't come all that way to watch his daughter marry "some shmuck" from the same village. He drives away as his daughter protests, to which Leonard calls after him, "don't worry where I'm from. My wife's gonna drive a Cadillac."
In Mississippi, two men from Fisk University approach McKinley. They're recording folk music for the Library of Congress and want McKinley to play for them. Upon listening to himself on the recording, McKinley feels like he's "meeting himself for the first time."
According to Dixon, McKinley was too big for the plantation. Therefore he leaves Mississippi and goes to Chicago. Once in Chicago, McKinley plays in the noisy street, though his acoustic can barely be heard.
From a window nearby, Geneva Waters (Gabrielle Union) yells down that "he's disturbing the peace." They start a romantic relationship and she gets him an amplifier, which brings attention to his playing.
Meanwhile, Leonard is opening up a club. Isabella Allen, who makes "race records" (recordings by colored artists), approaches him and gives him her card in case he finds any good singers.
In the street, Marion Walter Jacobs/Little Walter (Columbus Short) plays the harmonica with Jimmy Rogers (Kevin Mambo) playing the guitar. Muddy befriends the two and soon the three become an unstoppable group, calling themselves the All Star Trio, while others refer to them as the Head Hunters, talking about the way they "slice their competition." One day they go to Leonard's club and start a fight with the current trio playing. Although initially Leonard is hostile, throwing them out, he later tracks Muddy down because he wants Muddy to make a record.
Muddy and Leonard go to a radio station and bribe the DJ, who plays their "race record." Soon the record does well, and Muddy signs a contract with Leonard. To this Leonard gives Muddy a Cadillac as present, which starts a tradition. Shortly thereafter, Leonard's club mysteriously burns down. With the insurance money, Leonard starts a recording studio, Chess Records.
Little Walter makes his own record too. It does very well, going to the top of the charts, and Leonard gives him a Cadillac as well. Then Willie Dixon arrives as a songwriter, helping Muddy find more success. He also receives a Cadillac.
Little Walter makes another record and gets so famous that he comes across fakers. In line with his erratic nature, he shoots a fake Little Walter, though he doesn't get caught.
Chess Records continues to do well into 1955. It's name has become Cadillac Records because its artists receive Cadillacs for their success. Soon Leonard signs Howlin' Wolf (Eamonn Walker), who does extremely well. Wolf has a bit of an unfriendly demeanor, coming from a lack of trust for white men. Among other things, he opts to keep his old truck, saying he owns his truck, it doesn't own him.
During this time, Muddy is getting less popular, and he tells Leonard he needs money, since Geneva wants a house. Leonard says he'll take care of it. With all his fame, Muddy sleeps around. Geneva finds out one day when a woman drops of her baby, saying it is Muddy's and that she can't take care of it anymore. Geneva is heartbroken, but she loves Muddy. When Little Walter hits on her, she can't cheat.
Howlin' Wolf and Muddy begin to develop some tension. When Leonard tells one of his band members (a Hubert Sumlin, played by Albert Jones) to play lower, Wolf says not to command his band- he'll tell his band what to do. This seems to be a comment on how Muddy lets Leonard call the shots. In addition, Wolf flirts with a girl that Muddy had been interested in. Angry, Muddy opts to steal Sumlin from Howlin' Wolf. Meanwhile, Muddy gets Geneva their own house.
Somewhere else, Chuck Berry (Mos Def) tries to get into a white club, but finds that they won't let him in. The pin-up (a poster) makes him seem white and his ID says he's Indian, so they refuse to allow him entry, even though he plays to prove he is who he says he is. Then Walter provokes a policeman who calls him the N word. When Muddy disciplines him, Walter talks about how Wolf stood up for his bandmate and says he is leaving. He does so. Along with that, a shooter appears in a club Muddy and his group are playing in, and Wolf takes Hubert back.
Later Chuck Berry comes in for an audition, and Leonard likes what he hears. He says Chuck is a bit country but mostly just a different, new sound. He awards his new artist with a Cadillac. Chuck does exceptionally well, even integrating the airways. A white DJ says, "you may call this a race record, but I call it rock and roll." Chuck plays in segregated cities where white girls cross the rope that separates the floors, and even climb onto the stage. He refuses to give white people his money, instead eating cheap and sleeping in his car. Although Chuck doesn't drink or gamble, he has a problem with indulging in women, constantly sleeping with women- prominently young white girls.
Meanwhile, Muddy is getting less popular, though Leonard doesn't hesitate to help him out financially, saying that Muddy is "always number one" in his book. Dixon in his narration points out that while America was enjoying Chuck Berry's music, even putting him on American Bandstand, Rosa Parks was getting arrested and black people were getting lynched.
Leonard soon discovers Etta James (Beyonce Knowles), who is a feisty woman and a great singer. Leonard becomes interested in her, even buying out a restaurant so she could talk there with her supposed white father, Rudolf Wanderone. The latter doesn't want anything to do with her, saying her mother slept around. Leonard comforts Etta.
Chuck finds out that the Beach Boys stole the melody of his song and recorded their own song. He's angry about the ordeal, but is arrested before he can do anything. His charge is that he transported a minor across state lines for the purpose of prostitution. Leonard puts 10% of Chuck's royalties into Muddy's account, saying Berry won't miss it.
The Rolling Stones eventually come to record at Chess. They're happy to meet Muddy, saying his song inspired their name. They do well. However, Leonard's "golden egg," Chuck Berry, is in jail, and he needs a hit. So Leonard brings in Walter, though he is only a sideman now.
Etta records "At Last," which becomes a hit. But Revetta (Emmanuelle Chriqui), Leonard's wife, is suspicious of Leonard when she finds a bill about Etta's song. When Etta begins to miss radio appearances, Leonard wants to go find her. However, he had a dinner planned with Revetta. Muddy says he will check up on Etta, but calls Leonard when Etta is found unconscious. Leonard leaves in the middle of sex with his wife. At Etta's home, he finds that she was taking heroin. He kisses her, and Muddy and Geneva walk in. Muddy disapproves, and also says Leonard is screwing over his artists, just taking their money. Leonard objects, bringing up the Cadillacs he gave away.
Soon Chuck gets out of jail, but his peak is over. Even Elvis Presley has stolen his music.
At home, Leonard gets a call that someone is breaking into Chess Records. However, when he gets there, he gets beat up by anonymous black men. Walter gets beat up too, though somewhere else and because of gambling. Unfortunately, he dies soon after appearing at Muddy and Geneva's home.
Now times have changed, and Leonard decides to sell the company. Sadly, he dies of a heart attack while driving away from the studio. Although he didn't make a will, meaning everything goes to his wife and kids, he leaves the deed to a house he got for Etta, to Etta, showing that he did really love her, pleasantly surprising both Etta and Muddy.
Muddy and Dixon get called to go to England, and they opt to go, though Muddy is unsure about the trip, since it's a different country and he doesn't know how he'll know what the audience wants. However, they are greeted by photographers and a red carpet, which makes Muddy feel more welcome and less worried.
Dixon got a lot of money from writing hit songs, and he eventually buys the Chess Records studio.