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Young Jessica Fletcher’s life couldn’t be more ordinary. She teaches at the local high school while she and her loving husband, Frank, are raising their nephew Grady together. But when the beloved principal dies under mysterious circumstances, Jessica knows something is off and, for the very first time, investigates a death. Present-day Jessica returns to high school for a colleague’s retirement party and has fun seeing familiar faces. That is, until the colleague winds up dead - and his death has mysterious links to Jessica’s very first murder case.

Bestselling author Jessica Fletcher is in Tampa with her good friend, Cabot Cove's own Dr. Seth Hazlitt, who is visiting a renowned Cuban physician. Alvaro Vasquez is developing a potentially groundbreaking cure for Alzheimer's disease. If he's successful, his American backers stand to make millions. But there is a growing fear that the drug may fall into the hands of a powerful pharmaceutical company. Jessica attends a party at Vasquez's lavish home, but the celebration ends abruptly when guests witness Vasquez seemingly struck by lightning.

Jessica Fletcher has had plenty to worry about over her storied career, both as a best-selling novelist and as a part-time sleuth. But she's never had any reason to doubt her longtime publisher and trusted friend, Lane Barfield. When mounting evidence of financial malfeasance leads to an FBI investigation of Lane, Jessica can't believe what she's reading. So when it appears that Barfield has committed suicide, Jessica takes on the task of clearing his name. Sure enough, Jessica turns up several inconsistencies in the case against Barfield, as well as signs he might have been murdered.