As Calhoun rides on the train with General Sherman on his tour, Dave, Barnabas, and the entire population of one of the train's stops are taken prisoner by a former Confederate officer and his group, who plan to assassinate the General.
After one of Breed Pembrooke's two sons is killed accidentally while robbing the train station, the ruthless man has Calhoun and the train conductor kidnapped and taken to his makeshift "town" where he finds them guilty of murder and sentences them to death. But he plans to submit the men to his sadistic games before killing them.
A cave-in traps Nils, another crewman, and a little boy in a tunnel. While Dave and others work to dig them out, Calhoun and Barnabas rush to retrieve a batch of nitro to free them. But their trip becomes more dangerous than ever when their wagon wheel collapses and they must seek the help of a preacher who believes they are damned, and someone else who is determined that they not make it back alive.
A man who sold lumber to Calhoun's railroad has disappeared, and his brother thus refuses to unload the lumber unless and until he is found to prove the sale was made. Suspecting two renegade Indians who quit just after the man left, Dave sets out to find them, along with the seller's brother. The behavior of the owner of a trading post leads them to suspect the answers are to be found there.
At a stop in town, Calhoun is forced to shoot a man. Unaware of who he is, two men then hire him to kill---Ben Calhoun. Calhoun decides to play along with the plot in the hope of discovering who is behind it.
While the train is stopped in the town of Banner, where Calhoun is making a major business deal with town founder Big Jim Banner, Barnabas is attacked by Banner's son, who thinks Barnabas is one of the Claiborne boys with whom the Banners have a major feud. At first it seems to be a mistake, until Barnabas meets Jeff Claiborne, who looks just like him. Soon Barnabas, who was raised as an orphan, starts to believe that he may be a Claiborne as well.
Six people from a stagecoach board Calhoun's train, all in fear for their lives after being followed for miles by a notorious gunman, who also boards the train. Calhoun puts him off, but he keeps following, and won't reveal which of the people he has been hired to kill, leading each of them to paranoid fear which may be a worse killer than his gun.
Calhoun finds an eight-year-old Arapaho boy alive as the only survivor of a battle with the Shoshone. He wants to bring him back to his people, but the Shoshone want him brought to them, as he is the son and heir to the slain Arapaho chief. Calhoun fears that he will be killed if brought to them, but local townspeople, including a close friend, want to maintain the peace with the Shoshone and thus do as they ask---while others in the town want to use the incident to start a new war.
With Calhoun away, the train is taken over by a group of ruthless outlaws who demand that Dave turn over a large fortune in bonds that is being delivered. Dave tells them that they will have to wait for Calhoun to return with them, but that is a delaying tactic as Calhoun will not be back that soon and Dave may have to resort to other plans to save the lives of the crew and passengers.
Calhoun is under orders from President Grant himself to safely transport Pierre Le Druc, an associate of Mexico's deposed puppet emperor Maximilian, to a meeting with his French countrymen on the west coast. But Le Druc is a ruthless killer, and a Mexican general is also pursuing the train to capture Le Druc and bring him back for trial.
When Calhoun's railroad is given the contract to haul for a mining company, it effectively puts the owner of the old coach freight line, who had the contract before, out of business. The freight company owner's inept sons decide to get back at Calhoun by robbing the railroad of the mining company payroll, and they hire a ruthless gunman to help them.
Calhoun wins a high stakes poker game against outlaw gambler Dan Patrick. But Patrick says he does not have the money on him, and offers a beautiful young Spanish noblewoman as collateral. Calhoun agrees to leave the young woman with Barnabas as he goes with Patrick to retrieve the money. But Patrick has no intention of keeping his end of the bargain.
Calhoun learns that he is transporting three female prisoners to Kansas City, and that one of them is the only witness against a ruthless mob boss being tried for murder. But the man has no intention of letting her arrive to testify against him, and has put his associates on the trail and on the train to make sure of it.
Calhoun outbids his old nemesis Sam McGinty in an auction for a new boiler which both men need. But shortly afterward, the boiler is stolen at gunpoint and taken, along with Dave, to an impoverished town which needs the boiler to revive its only source of income. Dave soon finds himself in a predicament as he comes to sympathize with the townspeople.
Barnabas identifies his coworker and friend Billy Pardew as the killer of a store clerk, though only on the basis of his boots. The obviously biased judge, a man known to be too quick to hang defendants, asks Calhoun to act as Billy's defense when no attorney agrees to take the case. And Billy's uncles are determined to stop his being hanged any way they can.
Calhoun's acquisition of a right-of-way for the railroad is threatened when he takes the side of allowing a band of Indians---mostly old people, women, and children---to go through it on their way back from the reservation to their ancestral home. The townsmen who agreed to the right-of-way do not want them to cross it, and insist that Calhoun keep them only on the narrow strip he owns or forfeit it, and hence lose the railroad.
Ben puts himself in the center of a conflict when he decides to help French monks establish a vineyard. But trapper Ike Bridger and his friends see it as prime beaver habitat and are unwilling to give it up without a fight.
Calhoun realizes that four members of an outlaw gang have surreptitiously boarded the train. But he decides to not let them know he is on to them until he knows their plan, and can devise one of his own to stop them.
Young Frank Wyatt is accidentally shot in a fight with Barnabas, who thought he was behaving improperly with a young woman. Calhoun tries to take Frank to the nearest doctor by using the train, but Frank's powerful father forces both Frank and Barnabas off and takes them to his ranch. Though this action aggravates his son's wound, the elder Wyatt plans to kill Barnabas if Frank dies, even over Frank's objection.
Although Calhoun discovers that the man who saved Julie and Barnabas from ambush is a former railroad engineer branded as a traitor during the Civil War, he still decides to hire him, despite Dave's objection and his own suspicions. Unfortunately, the man still has his old associates riding with him and they are all planning to steal the gold that the train is carrying.
The ownership of a luxurious railway car is disputed so Ben takes possession of it even though it contains passengers. He ruins the plans of an outlaw gang that had plans to hold everyone and the car for ransom.
A dying marshal deputizes Dave (who in turn also deputizes Calhoun) to transport his prisoner to Doan's Junction to be tried for murder. But other members of the killer's gang have boarded the train and are planning to break him free. The prisoner also sees an opportunity for escape in a young woman who is being forced into marrying a wealthy man and clearly doesn't want to.