Bill and Major Adams plan on going hunting with a friend but when he is not home they suspect a renegade party of Cheyenne who have broken the peace treaty and the wagon train may be their next target.

Flint meets Chris Hale alone on the prairie. Hale has just found his entire family massacred by Indians, and Flint asks him to join the wagon train. However, the company that owns the wagon train has hired a new wagonmaster, Jud Benedict. Benedict is a ruthless and brutal tyrant who puts time above all other considerations, and does not care how many people are left behind or even die in the process of heading to the final destination as soon as possible. He has also hired unscrupulous gunmen to enforce this goal by brutalizing slower people, or anyone who stands up to him. It is revealed that Hale has also been a wagonmaster, but has retired from the job and does not ever want such a responsibility again. Still, people on the train are looking to Hale to stand up to Benedict.

When the wagon train passes through town, habitually drunk Jeremy Dow finds that his past has caught up with him. His choices: continue running, or face the demons from his past when he is confronted with this wife and son on the train.

Looking forward to some time off, Flint heads towards the town of Monument but runs into an old man and some kids whose parents were just massacred by some Mescaleros and they're running low on supplies especially milk for the baby.

The Santee family---Will, his mother, and his younger sister---join the wagon train under a false surname. They have been forced out of town after town because of a terrible thing a family member did. They confide in Hale, Hawks, and Charlie, who agree to keep their secret from the others on the train. But it soon comes out anyway, and things get complicated when Will falls for a young woman from the wagon train.

Saul Bevins, a blind doctor traveling with his son, his sister, and his dog, asks to join the wagon train. Many others on the train object that he will slow them down, but Hale agrees to let him ride at least until the next settlement, at which time the entire wagon train will vote on whether he should continue. On the way Bevins is forced to overcome many obstacles.

Flint comes across four survivors of an Indian massacre, the two Ellison sisters and two Carder brothers. One of the sisters is deaf and mute. The brothers are the only survivors of their Army unit. The older brother, Joe, wants to desert and take advantage of the situation in order to break away and look for gold. The younger brother, George, is simple-minded and good-hearted but loyal to the older one who raised him. Flint tries to lead the four to safety, but Joe Carder tries to mislead the Ellison sisters into believing that Flint is leading them into danger.

While preparing to return to St. Joseph, the men read the story "Wagon Ho" written and printed by Samuel T. Evans about his trip as a naive young Irishman headed west and his experiences and adventure on the trail.

Gabe Henry and his son have been sorely missing the female touch over five years now. Finding a wife during a stopover is his top priority but his choice is known to Major Adams and he does not approve.

Wounded Bill Strode arrives in camp looking for Flint. Strode, who saved Flint's life in Abilene, asks Flint to help him get to Fort Kearny. Flint learns the itchy Strode is being hunted by bounty hunter Earl Packer and Strode has changed.

The leaders of the wagon train are taken aback when they see a woman asking to join the wagon train who is the twin of Major Adams one and only love who died in his arms.

When actress Nellie Jefferson joins the wagon train, her incessant demands for special treatment come to grate on Hale and Hawks, but Wooster is totally smitten with her. Meanwhile a fanatical man from her past is following her, talking about how she will meet her fate like the biblical Jezebel.

When someone yells horse thief, Flint shoots a man only to find he is the husband of a childhood friend. Flint learns the man is mayor and highly respected. The question of whether he killed an innocent man bothers him and the man's son.

A green Army Colonel wipes out a village of Comanche women and children thinking he is getting revenge. The wagon train must face on the one side a swollen river they must cross or a Comanche chief on the other who seeks justice.

An Italian immigrant couple needs help in transporting water for their grapevines to California. Unfortunately, the two men who offer the use of their wagon plan to steal the treasure they've heard the immigrants are carrying in return for their services.

A flashback episode - Chris Hale's duties as wagonmaster require him to leave his family in their prairie home.

Bill Hawkes is leading 3 wagons through Indian territory. They run into trouble with Mexician bandits lead by Lee Marvin. When the 2 groups must band together to fight off an Indian attack, certain biases & assumptions are thrown away.

A retired Captain and ten boys join the wagon train on their way to California. Hitching a ride was all he thought he was involving the boys in until he meets one man on the train with a secret resentment.

With his clever tall tales, old prospector Henry Shannon talks Charlie Wooster into coming with him to search for a gold mine. When Hawks finds out about this, he rides out after the two men, along with Shannon's grandson Duke. Also following the old men are three men who hope to grab the gold for themselves.

Arrogant British Colonel Albert Farnsworth causes an uproar in camp and puts the wagon train in danger of Indian attack, resulting in the capture of a young girl by the Cheyenne and the mortal wounding of his long time aide.

Dr. Craven feels he can't perform surgery any longer. When he joins the wagon train and his services are desperately needed, he realizes he may be wrong after Major Adams gives him a history lesson.

Flint discovers a badly wounded waitress on the range and takes her to a doctor, where he finds the evil town's owner wants to hang her without trial, because he suspects she murdered his son.

A married couple use the wife's innocent face and winning way with children to gain the trust of their companions on the wagon train so that they won't be suspected when the husband pulls off a bank robbery nearby.

Flint goes to visit Eleanor Culhane, an old flame of his who had been married to a notorious gunman. He finds everyone in the town she lives in shunning her, and unwilling to discuss her, because they blame her for her husband's misdeeds and the shame he caused the town. When Flint finds her they begin to rekindle their romance. But then her husband, thought dead for the last five years, shows up in town. And Flint realizes there is another side to Eleanor that he was unaware of as well.

The story of the women of the wagon train and the unforgiving prairie through which they pass. Who will endure, and who will give up? Who will live, and who will die?