Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract and are a relatively recently identified category of mesenchymal tumors. Germline mutations in a number of different genes predispose to GIST. This article discusses familial GIST syndrome, Carney triad, Carney-Stratakis syndrome, and neurofibromatosis type 1, and addresses the recognition of an inherited predisposition in GIST patients.