In seeking to paint "a fresco on the birth of a great nation", Sergio Leone turned to the Hollywood western, rather than American history, for his inspiration. Set at the time when the dollar replaced the bullet as the currency of the frontier, this breathtaking tale of progress, greed and revenge clearly bears the influence of John Ford's seminal silent western The Iron Horse (1924). The story focuses on brutish gunfighter Frank (Henry Fonda), who dreams of becoming a tycoon, but is still prepared to resort to trusted methods to drive widow Jill McBain (Claudia Cardinale) off the land coveted by a ruthless railroad company. However, Frank must also deal with a mysterious harmonica player (Charles Bronson), as well as sympathetic outlaw Cheyenne (Jason Robards), if he is to achieve his goal. The screenplay was based on an original treatment by Bernardo Bertolucci, Dario Argento and Leone himself; despite such impressive credentials, however, much of the action was improvised around the mood of the score, which Ennio Morricone had composed in advance. No wonder many critics described the film as an operatic masterpiece.

As the railroad builders advance unstoppably through the Arizona desert on their way to the sea, Jill arrives in the small town of Flagstone with the intention of starting a new life.