Bridesmaids and IT Crowd actor Chris O'Dowd will lead the show's cast, who have been filming in LA and the UK. The show is scheduled to air in the US and UK in spring 2013.
Family Tree will centre on O'Dowd's character Tom Chadwick, a 30-year-old who has just lost his job and girlfriend. After discovering a mysterious box left by a great-aunt, Tom sets off on an adventure around the world as he investigates the unusual stories and characters from his family's past.
The show will be filmed in a single-camera, improv, documentary style - a technique that Guest pioneered and is most famous for.
Also among the cast are Nina Conti, Tom Bennett, Ed Begley Jr, Maria Blasucci, Matt Griesser, Don Lake, Michael McKean, Lisa Palfrey, Amy Seimetz and Fred Willard, as well as co-writers/co-creators Christopher Guest and Jim Piddock.
Guest said: "I am... delighted to welcome myself to BBC Television. I am very lucky to be working with an incredibly talented cast. Chris O'Dowd has been on my radar ever since he was a child actor in Wales."
O'Dowd added: "I'm terribly excited and monumentally under-qualified to work on an improvised show with Chris Guest. I call him Chris 'cos we are friends. He calls me George. I don't know why."
BBC Two boss Janice Hadlow said: "I am delighted to welcome Christopher Guest to BBC Television. It will be his first television series for British audiences and one I am proud to have here on the BBC. It has a stellar cast led by the fantastic Chris O'Dowd and is an exciting collaboration with NBCU International and HBO. Family Tree will form a key part of the channel's comedy next year."
Watch a This Is Spinal Tap clip below: