Guido Contini (Daniel Day-Lewis) is a gifted Italian filmmaker who, at the age of fifty, has developed writer's block and urges all the women in his life, alive and dead, to help him with it. His mind wanders to his unfinished set, where dozens of dancers and the film's leading ladies appear: Claudia Jenssen (Nicole Kidman), his leading lady; his wife Luisa; his mistress Carla (Penélope Cruz); his costume designer and confidant Lilli (Judi Dench); his beloved Mamma (Sophia Loren); Stephanie (Kate Hudson), an American fashion journalist from Vogue; and Saraghina (Fergie), a prostitute from his childhood; ("Overture Delle Donne"). It is 1965, and at the famous Cinecittà movie studios, in Rome, 'everyone has questions for Signor Contini.'At a press conference at the Hotel Excelsior on the Via Veneto, he's charming and colorful, avoiding any clear answer on his new movie, his ninth with producer, Dante (Ricky Tognazzi), tentatively entitled Italia. Here he meets Stephanie, a Vogue fashion journalist, with whom he begins a flirtation. Escaping the biting probes of the reporters, he creates an elaborate fantasy ("Guido's Song"), where he explains that he wishes he were young and energetic once again, since his talent was better then.He escapes the press conference and arrives at the Bellavista Spa Hotel. While being examined by the doctor (Roberto Citran), he receives a call from Carla, his mistress ("A Call from the Vatican"). She describes her desire for him, as he listens on the other end. She arrives at the spa, expecting to share his suite, but is upset to find that she's staying in a shabby Pensione by the train station. Meanwhile, Guido learns that a Cardinal is also staying at his hotel and tells the cardinal's assistant to arrange a meeting.However, Dante soon arrives at the spa and escorts Contini to a banquet hall where the entire production team is assembled to help him prepare for his film. He sees Lilli, his costume designer, and begs for inspiration, while criticizing the costume she's in the middle of making as not being something an Italian woman would wear. She reminds him of Luisa's (Marion Cotillard) (Guido's wife) birthday the previous day and disagrees, saying that it reminds her of Folies Bergère, a Parisian music hall that featured showgirls, where she 'learnt her art' ("Folies Bergères").The Cardinal agrees to meet him and advises him to lead a more moral life and look to his youth for inspiration. Guido remembers Saraghina, a prostitute whom he and his friends paid to teach them the art of love and sex ("Be Italian"). Young Guido is caught by his schoolteachers/priests and whipped by his principal. He awakens on top of Carla, in a fit of anxiety and abruptly leaves to meet his production team for dinner. She wants to come, but he vehemently refuses, reminding her that they don't want to hurt either of their spouses.At dinner, he's happily surprised to see Luisa, who has come at Lilli's request. He embraces her and wishes her a happy birthday, promising that when she returns home, the house will be filled with flowers. She sits, and the young priest from earlier, who recognizes her as one of Guido's earlier actresses, joins the table. In song, Luisa explains how she's become a different woman to be Guido's wife, abandoning her acting career to be at his side ("My Husband Makes Movies"). She then notices Carla entering the restaurant and leaves immediately, saying she feels tired. Guido doesn't understand why and follows her, asking what's happened. She ignores him and when he returns to the restaurant and sees Carla, he finally understands. He demands that Carla go back to the Pensione, and she leaves, heartbroken.When Guido goes to the suite to try to smooth things over, Luisa refuses to listen. He meets Stephanie, who has tracked him down. Guido and Stephanie continue to flirt, and she describes her love for his movies and how fashionable he makes everything seem ("Cinema Italiano"). She leaves her room key in his pocket. While in her room, watching her undress, he realizes how much he cares for his wife and leaves. He returns to the suite and promises that he's done with cheating. Luisa embraces him, but he's called away to help Carla, who's overdosed on pills. The doctor comments how reckless and immoral Guido is, which Guido doesn't contest. He stays with Carla until her husband arrives. He returns to the hotel to find that Luisa has left and the crew has returned to Rome to begin filming.His mother returns to him to advise him to repair his life ("Guarda La Luna"). He calls Luisa from the studio to beg her to come to the screen testing that evening. She hangs up without response. He arrives at the set to film shots of Claudia in her costumes. She does a few takes, but leaves, saying she'll return when she reads the script. They're followed by paparazzi, but Guido manages to lose them. Claudia realizes that there is no script, and they take a walk. She asks him what he wants the film to be about, and his description closely resembles his own ordeal: a man lost and in love with so many women. When they stop to rest, she tells him that she loves him, but he is unable to love her ("Unusual Way"). Claudia tells him he doesn't see the real her, only the movie star he has created for the masses. She leaves.He returns to review screen tests of new actresses and keeps looking to the back to see if Luisa has arrived. He's relieved when she finally does. She watches and is heartbroken to see him say something in a clip to an actress that he'd said to her when they first met. When everyone leaves, she explains to him that he's reminded her that she's not special, just another link in the chain and leaves him ("Take It All"). He finally comes to terms with his mental block ("I Can't Make This Movie"), realizing that he's lost everything: his wife, his muse, his talent, and has nothing to make the movie. He apologizes to the staff that there was never a movie, just an idea, and has the set destroyed before leaving Rome.Two years later, Guido is in a cafe in Anguillara looking at an advertisement for a play starring Luisa. He waits outside the theatre that night and watches her leave with a man. He walks with Lilli a few days later and tries to find more information about her. Lilli tells him that she's not going be to be the middleman for them, implying that Luisa asks for him as well. She asks if he will ever make a movie again. He says that he won't because he wouldn't know what to make, except a movie about a man trying to win back his wife. Lilli says that that's a good start and the costumes won't be too bad either.Guido returns to his element, passionate about a story once more. As he speaks with his actors about the scene, his nine-year-old self (Giuseppe Spitaleri) gathers the cast of Guido's life together. As Guido takes his place in the director's chair, the cast of Guido's life assemble on the scaffolding behind him, culminating with the arrival of his mother and nine-year-old Guido running to sit on the older Guido's lap ("Finale"). Luisa arrives without being seen and watches in that background, happy to see Guido back to his old self. She smiles as he is raised on a crane and calls, "Action!"