Ghost Whisperer is an episodic series that follows the life of Melinda Gordon, a young woman who has the ability to see and communicate with the dead. Each episode deals with one or more ghosts seeking Melinda's help in relaying a message or completing a task that will put the spirit to rest, and allow them to "cross over" into The Light, a metaphor presented by the show as its conception of Heaven. Crossing over is when a spirit leaves earth and goes to heaven.

Despite the episodic structure of the show, plot lines that span two or three episodes (normally during season openers and finishers) develop and progress throughout the rest of the season. The first season arc introduced the show's first antagonist, Romano, a negative entity in a black hat, who attempted to do the exact opposite of Melinda and gather earthbound souls and bring them to the Dark Side. The story climaxed in the season finale when a plane crashed in Grandview, and Melinda and Romano both attempted to sway the souls to the Light, and staying on earth, respectively. Her Best Friend Andrea Marino was killed in the plane crash and, in a story that would carry over to the second season, was being swayed by Romano to stay earthbound.

In the second season, two new characters (Delia Banks and Professor Rick Payne) are introduced, both of whom, by season's end, come to learn of Melinda's power and become survivors that ghosts want messages passed to through Melinda. The second season arc revolves around the thinning "veil" between the living and the dead, evident in certain situations in second season episodes. By the end of the season, a second Ghost Whisperer was introduced. His arrival in Grandview sets the final events of a disastrous prophecy in motion, and the strengthening of the dark side over the Light.

The beginning of each episode normally revolves around Melinda first encountering the ghost(s) that will be crossed over in the episode. In their normally brief appearances, Melinda collects clues she later researches. After gaining a significant piece of information that drives the episode's plot further, the ghost(s) normally open up to her, and tell her how it is she can help them find peace. Often, the messages the ghosts want Melinda to pass are confusing and as a result, she is normally met with questions and scepticism by those she is trying to give the message to the families, friends and lovers of the ghosts. By the end of each episode, Melinda is usually able to complete her task and cross the ghost(s) from the respective episode over.