During the years following the Civil War, banks and trains become the targets of the James-Younger gang, outlaws who terrorize the Midwestern United States. The band of robbers is led by Jesse James and Cole Younger, along with several of their brothers.
Young, starstruck Robert Ford (Casey Affleck) seeks out Jesse James (Brad Pitt) when the James gang is planning a train robbery in Blue Cut, Missouri, making unsuccessful attempts to join the gang with the help of his older brother Charley (Sam Rockwell), already a member. The train turns out to be carrying only a fraction of the money originally thought, and Frank James (Sam Shepard) tells Charley Ford that this robbery would be the last the James brothers would commit, and that the gang "gave up their nightridin' for good." Jesse returns home to Kansas City, bringing the Fords, Dick Liddil (Paul Schneider) and his cousin, Wood Hite (Jeremy Renner). Jesse sends Charley, Wood and Dick away, but insists that Bob stay. He wanted the younger man just for his help in moving furniture to a new home in St. Joseph. Bob becomes more admiring of James before being sent back to his sister's farmhouse, where he rejoins his brother Charley, Hite, and Liddil.
A group of Confederate guerillas are trying to raid the Union Army, very late in the American Civil War. The southerners are ambushed, but thanks to the sharp-shooting of Frank James (Gabriel Macht) and the distracting and at the same time clever antics of Jesse James (Collin Farrell), the guerillas manages to survive & pull through. The James brothers, along with their war buddies, the Younger brothers, congratulate themselves, but (during the ride to reconnect with their unit) are surprised to learn that their army has pulled out, General Robert E. Lee had surrendered the previous day at Appomattox, and the war is over. The group decides to return home to their families and farms.
Milford Farnsworth (Hope) is a bumbling insurance agent who unknowingly sells a life insurance policy to the outlaw Jesse James (Wendell Corey). Farnsworth is sent out West to protect the insurance company's investment by "protecting" James.
Jesse (Robert Wagner) and Frank James (Jeffrey Hunter) ride with their gang into Northfield, Minnesota for a raid. While robbing a bank, gun fighting breaks out and two of the gang are killed. The James brothers and another gang member head out of town and hide out while investigators from the Remington Detective Agency search for James to receive a $30,000 reward. While the three are hiding, the film tells the story of how the James brothers came to be criminals in flashback.
A railroad representative named Barshee (Brian Donlevy) forces farmers to give up the land the railroad is going to go through, giving them $1 per acre (much less than fair price) for it. When they come to Jesse's home, Jesse (Tyrone Power) tells Barshee that his mother Mrs Samuels (Jane Darwell) is the farm's owner.
After the death of his outlaw brother, Jesse (played in the earlier film by Tyrone Power), Frank James (Henry Fonda) seeks revenge on his killers, Bob and Charlie Ford (John Carradine and Charles Tannen).
L'homme d'affaires Phineas Krager arnaque les paysans en leur offrant des terres puis en les obligeant à les racheter à un prix exorbitant. Jesse James défend les fermiers en volant à Krager son propre argent afin de payer les sommes qu'il réclame. Dès lors, sa tête est mise à prix. Bien qu'étant un vieil ami de Jesse et des paysans, le shérif Gabby Whitaker est obligé de l'arrêter lorsqu'un habitant le reconnait en plein milieu de la ville.
Délégué par le président américain Winston H. Jameson pour sécuriser Daisy Town afin de pouvoir faire la jonction du chemin de fer est-ouest, Lucky Luke retourne dans sa ville natale désormais dominée par l'escroc Pat Poker. Hanté par de vieux démons, il voit ses ambitions d'y faire le ménage bientôt contrariées par l'arrivée de vieux ennemis.
During the late 1880s, Dr Frankenstein’s evil granddaughter Maria has moved to the American West with her brother Rudolph, in order to use the prairie lightning storms in her experiments on immigrant children snatched from a dying town. Maria is very much in charge, killing the children and replacing their brains with artificial ones, intending to revive them as her slaves. Rudolph however, is reluctant to help his sister, but is too afraid of her to do otherwise. After a number of failures (owing to Rudolph secretly poisoning the victims as soon as his sister revives them), they are finding it increasingly difficult to hide the trail of bodies. Down the road, Mañuel Lopez and his wife Nina decide to leave town with their daughter Juanita because of the frequent disappearances, the latest of which is that of their son.
In the mid-1870s, outlaws Jesse James, Cole Younger and their brothers are granted amnesty by the Missouri legislature, sympathetic to the troubles created for all citizens by the American Civil War. The bankers victimized by the James and Younger gangs are vehemently opposed to this action and hire a Pinkerton agent to follow the outlaws' every move.