Dr. Mike and the citizens of Colorado Springs look forward to the advantages a train could bring to their small town, but Sully and the Cheyenne fear progress could lead to their demise. While Loren and Jake are creating a false campaign of the town's highlights to lure the railroad developers to the area, Mike and Sully disagree about whether or not they should build their future and their new home in a town undergoing such change. While the engaged couple searches for a compromise, Colleen befriends a Chinese railroad laborer, named Peter, who has encountered hostile discrimination during his stay.

When Loren sets out to prove he's not too old, and Brian wants to prove he's old enough, the two embark on individual journeys that intersect. Loren shocks everyone when he announces that he's going to travel to Bolivia, to prove to himself and to everyone else that he's not too old for the treacherous adventure. While he's away, Brian takes off on his own little adventure -- to camp out alone at night and brave the elements. But an unexpected travel companion -- a grizzly bear -- unites the two "men" in a shared adventure neither anticipated.

Loren's sister, Miss Olive, has died and bequeathed her cattle to Matthew who, along with Dr. Mike, Sully, Colleen, Brian, Loren, Robert E, and Grace, attempts to bring the cattle back to a ranch near Colorado Springs.

The Cattle Drive continues with various difficulties to overcome including conflicts between Matthew and Sully, cattle rustlers, hungry Indians, and a prairie fire. Dr. Mike delivers a calf, and Sully helps her clean up afterwards.

Elizabeth sends crates of books from Michaela's deceased father's collection, prompting her to open a public library. Many become alarmed at the content of some of the books and want to prevent people from reading them.

Brian rescues a man from a trap who has horrific burns to his face from a train crash. Michaela decides to perform reconstructive surgery to repair his face.

Cloud Dancing and the rest of the Cheyenne are told to move to a reservation where they would be dependent on handouts. Dr. Mike, Sully, and the children head to Washington to lodge a complaint and get the order changed.

Arriving in Washington, Dr. Mike and Sully find it difficult to find anyone to listen to their concerns. Sully is arrested for army desertion while a plot against the president is overheard. Michaela must break Sully out of jail to expose the conspiracy.

When money becomes short for Sully, he tries everything to make ends meet rather than accept help from Dr. Mike.

Dr. Mike and Sully are traveling through obnoxious Native American territory when their stagecoach is robbed and they are abandoned. With them are a just married Kid Cole and Sister Ruth as they try and reach home for Thanksgiving. Evading hostile tribesmen is only the beginning.

Dr. Mike discovers a lump in Dorothy's breast and tries to convince her to have surgery. Hank tries Ladies Night at the saloon, and Jake and Loren have a plan to get free drinks. Colleen deals with hurtful boyish pranks from classmates.

Dr. Mike has a hard time accepting Dorothy's decision not to have the surgery that will save her life. Jake tries to escape the two men who kidnapped him.

The town's Christmas spirit is in question when a family who are Jewish immigrants moves to town.

Sully is appointed Indian agent to the Cheyenne and approaches it in an idealistic fashion. When the food intended for the tribe is diverted and illegal alcohol is plentiful, Sully becomes angry. He vows to discover the truth with the help of Dr. Quinn and her family.

A newspaper report of a comet's imminent collision with Earth causes hysteria in town over the end of the world.

Sam Lindsay, an older independent woman, decides to end her medical treatment and take off into the wilderness. Dr. Quinn accompanies her and learns from the journey. Myra Bing goes into labor and Colleen finds what she is capable of.

Colleen and Brian's biological father Ethan returns to town with a new wife, intending to take the children away from Dr. Quinn. The children don't want to go but a court hearing seems to work against Sully and Dr. Mike, who they consider their parents.

Colleen and Brian run away to keep their father from taking them away from Dr. Mike and Sully. After they are found it's discovered Colleen has developed pneumonia. Dr. Mike realizes she has to let them go to save them.

The town puts on a production of "Romeo and Juliet". Brian tries to learn what love is so he can write a paper for school.

Dr. Mike convinces Robert E to take a job fixing a train boiler, then finds out it is a dangerous job.

A teenage Belle Star robs the saloon with the Younger brothers and is shot. Dr. Mike takes her home in an effort to show her a real home life, attempting to turn her from her life of crime.

An abrasive Dr. John Porter arrives in town after hearing of the discovery of dinosaur bones. After learning they were found in a sacred Indian burial ground, he proceeds to spoil grave sites under the protection of the US Army. Cloud Dancing and the Cheyenne retaliate by taking the remains of the white settlers.

When Dr. Mike becomes the substitute school teacher, the town gets upset when she teaches the children about evolution.

Dr. Mike and Sully convince Chief Black Kettle that he should move his starving people to a new reservation. Dr. Mike and Sully are both working on wedding presents for each other.

When Dr. Mike and Sully hear there is trouble for the Cheyenne at their new home, they travel there with Cloud Dancing only to find the whole tribe was massacred. Dr. Mike is devastated after the massacre because she felt she should have stopped it.

While on his way to resign as Indian Agent, Sully discovers Loren badly injured in the wilderness and must battle his own despair in order to save him. Meanwhile, Dr. Mike is worried about Brian who is consumed with his efforts to build a flying machine.

Dr. Mike and Sully go to Rev Johnson for a honest discussion regarding their upcoming marriage.After originally agreeing they have no conflicts, the couple begin reliving their past difficulties via prior show clips since they first met.

The town of Colorado Springs is preparing for an event of a lifetime, the marriage of Sully and Dr. Mike. Unexpected guests include Dr. Mike's mother Elizabeth Quinn and two of her sisters Rebecca and Marjorie. They have brought with them enough Boston finery to pull off a splendid society wedding. Meanwhile General Custer has put out a bounty on Cloud Dancing which could interfere with the wedding.

Bolstered by the long-awaited arrival of the railroad, the citizens of Colorado Springs busily prepare for the biggest social event in the town's history, the wedding of Dr. Mike and Sully. The first train carries some surprise visitors, Dr. Mike's mother, Elizabeth, and sisters Marjorie and Rebecca, who have unexpectedly traveled all the way from Boston for the occasion. However, their elaborate wedding plans threaten to ride roughshod over the townsfolk's more homespun arrangements. Sully, meanwhile, is crestfallen to learn that Gen. Custer has placed a bounty on the head of his close friend Cloud Dancing, who he had planned to have as his Best Man.