The first episode of the Starz co-production with Lionsgate Television is to be directed by filmmaker Gus Van Sant in his TV helming debut.
The eight-episode season is to premiere in October on Starz.
It is about "the Machiavellian machinations of a fictional Chicago mayor with a dark secret," the cable network said in a news release Wednesday.
"Cheers" and "Frasier" star Grammer will make his dramatic TV series debut as Chicago Mayor Tom Kane.
Connie Nielsen will play Kane's wife, Meredith, a formidable Chicago power in her own right. Jeff Hephner will play ambitious young politician Alex Zajac.
Hannah Ware will play the Kanes' estranged daughter, Emma, and Kathleen Robertson will play Kane's supremely organized aide, Kitty O'Neil.
"What drew us to 'Boss' is its almost classical dramatic story, full of complex, complicated characters and a story that will be fun to follow," Starz Media Managing Director Carmi Zlotnik said in a statement Wednesday. "Kelsey Grammer as Kane is the perfect match of actor and role, and having a great storyteller like Gus Van Sant at the helm means this series will be unique as well as entertaining."