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- Hey, It's That Guy!: Recurring guest Harry McGraw is a lot more recognizable as Law and Order's Lennie Briscoe. Other well-known guest stars who had later roles:
- Kate Mulgrew of Star Trek: Voyager as a Rich Bitch who killed her husband/lover. Twice.
- Rene Auberjonois of Star Trek: Deep Space Nine played a murderer. And a professor character in one of Jessica's novels. And also a Southern doctor.
- George Takei of Star Trek played a janitor whose collection of celebrity trash helps Jessica.
- Leslie Nielsen appeared twice in two consecutive seasons, first as a captain of a cruise ship on which Jessica was a passenger, and then as a treasure-hunting old friend of Jessica.
- John Astin from The Addams Family appeared at least twice as the same character.
- Kevin Sorbo from Hercules: The Legendary Journeys as a VR game designer.
- Neil Patrick Harris from Doctor Horribles Sing Along Blog as a young fantasy writer who delivers Jessica's groceries.
- George Clooney and Julianna Marguiles each appeared on the show, separately, years before their success on ER.
- Courteney Cox of Friends as Jessica's great-niece by marriage, the granddaughter of her late husband Frank's brother.
- William Christopher from MASH was a birdwatching enthusiast who turned out to be a cold-blooded murderer.
- Vicki Lawrence appeared twice, the first being notable as her character was named Phoebe Carroll.
- Claude Akins, best known as Sheriff Lobo (no, not that Lobo), played recurring character Ethan Cragg in the first season.
- Eileen Brennan guest stars in "Old Habits Die Hard". As a politician's wife. With a secret. And who's willing to kill to protect it.
- "The Murder of Sherlock Holmes": One of the thugs who tries to mug Jessica in the alley is none other than a young Andy Garcia!
- Name's the Same: "Old Habits Die Hard" has a seemingly-Jerkass boyfriend character named Michael Phelps.
- In "Murder at a Discount", George Segal's character is named Dave Navarro.
- What Could Have Been: Jean Stapleton, better known as Edith Bunker, was first offered the role of Jessica Fletcher. Stapleton passed - ironically, given that she's on record as being unhappy with her Typecasting as Edith, and this show likely would have rescued her from that fate. In any event, the producers then offered the role to their second choice, Angela Lansbury, who gratefully accepted.
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