Over the last decade, gastrointestinal stromal tumors (GISTs) have evolved from histogenetically obscure gastrointestinal mesenchymal tumors to well-defined tumors with distinctive clinical, morphologic, ultrastructural, histogenetic, and molecular characteristics, for which targeted therapy is available. This is largely attributable to the discovery of CD117 overexpression and activating mutations in c-kit or platelet-derived growth factor alpha genes in most of GISTs. The availability of specific diagnostic tests and targeted therapy for GISTs has led to an increased awareness of these tumors. At the same time, the list of potential GIST mimics has lengthened considerably and it has become increasingly important that GISTs be distinguished from their mimics because correct diagnosis has implications for both treatment and prognosis. The purpose of this review is to provide an update of the expanding differential diagnosis of GISTS, to draw attention to unusual GIST variants, to provide a practical approach the differential diagnosis of GISTs and to highlight some of the challenges faced by pathologists in resolving this differential diagnosis.