Michaela Quinn, a female doctor in post-Civil War Boston, Massachusetts, finds more than she bargained for when she answers an ad for a doctor in a small town in the Colorado territory.

A wandering cowboy abandons his baby boy and leaves him in Dr. Mike's care.

The railroad hires men to kill off all the buffalo, which the Cheyenne need to survive, and Sully gets hurt when he tries to stop the men.

When Cheyenne medicine man Cloud Dancing is wounded by General Custer, who intends to hang him, Sully and Dr. Mike join forces to help him escape.

While hunting, Jake accidentally kills the Cheyenne brave Little Eagle and Sully tries to keep the peace between the Cheyenne and the town.

The army brings supplies to the Cheyenne as an offering for their land. Dr. Quinn advises them to take the supplies in order to ease their suffering through the harsh winters. However, the supplies harbor a hidden surprise for the Cheyenne.

A troop of buffalo soldiers comes to town and with them the idea that the government was using them instead of white soldiers, because it was felt they were more expendable.

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.

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.

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.

When Colleen, who is working on a college paper, asks Dr. Mike to recall her most memorable case, Dr. Mike looks back on the five turbulent years she's lived and loved in Colorado Springs. As they sit with Andrew, who is mysteriously ill at the clinic, Dr. Mike reminisces about her tumultuous career -- its successes and its failures -- and realizes how many divergent cases she has seen and treated. When Andrew's condition takes a turn for the worse, Dr. Mike warns Colleen about the fine line between emotional involvement and professional detachment, an issue with which she has long struggled in the frontier town that's now her home.