He rose to fame in the 1980s playing the whimsical, child-like character on TV and in movies.
"Last night we said farewell to Paul Reubens, an iconic American actor, comedian, writer and producer whose beloved character Pee-wee Herman delighted generations of children and adults with his positivity, whimsy and belief in the importance of kindness," according to a statement posted to his Facebook.
"Paul bravely and privately fought cancer for years with his trademark tenacity and wit. A gifted and prolific talent, he will forever live in the comedy pantheon and in our hearts as a treasured friend and man of remarkable character and generosity of spirit."