I’m thinking of people like Michael C. Hall, Michael Chiklis, Timothy Olyphant, and others in their category where the series they were key members of have passed away.
The one who comes immediately to my mind is Olyphant and Justified after his stint in Deadwood. Who’s had better follow-up work than Tim?
The flip-side of the issue would be those gifted actors whose recovery from their initial success has been slow in coming. Donal Logue in Terriers is an example.
Either Tom Hanks (Bosom Buddies) or Johnny Depp (21 Jump Street).
John Travolta - Welcome Back, Kotter.
Robin Williams - Mork & Mindy.
Terriers was Logue’s followup to his breakthrough show, Grounded For Life.
Bruce Willis, Moonlighting.
Jennifer Aniston?
Clint Eastwood - Rawhide
This question seems almost unanswerable… do SNL alums count?
Norman Reedus had a string of B-movie roles after appearing in The Boondock Saints but has found immense popularity as a lead character on The Walking Dead.
Some of them, for sure. 
George Clooney - ER
Will Smith - The Fresh Prince of Bel Air
Leonardo DiCaprio - Growing Pains
Bryan Cranston may have gotten a small start in Seinfeld, but his ‘breakout’ was in Malcolm In The Middle and his best success has been in Breaking Bad
Alyson Hannigan - BtVS - American Pie franchise, How I Met Your Mother.
Courtney Cox - Misfits of Science (or if this isn’t considered “breakout” enough, Family Ties)
Debbie Allen - 3 Girls 3
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Danny Devito has a record most would envy. In spite of many obstacles (physical appearance and age being the biggies) he’s had roles in several BIG movies and been behind the scenes in many others and is currently starring on a major cult hit.
I think I’d go with Friends for her breakout, but I’d also call it her most successful (but then, I don’t watch Cougar Town).
Tim Allen - Home Improvement. The show launched him into a successful movie career, including Galaxy Quest and The Santa Clause franchise.
Michael J. Fox - Family Ties