Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract. Aspects of the morphology and immunophenotype in GISTs resemble those in the interstitial cells of Cajal (ICC), which are a specialized cell type responsible for coordinating peristaltic activity throughout the gastrointestinal tract. Therefore, it is possible that GISTs result from transformation of nonneoplastic progenitor cells that would normally differentiate towards an ICC endpoint. Activation of the KIT receptor tyrosine kinase is required for differentiation and proliferation of nonneoplastic ICC, and oncogenic KIT mutations are a crucial event in the development of most GISTs. These mutations can involve either the extracellular or intracellular domains of the KIT receptor, giving rise to conformational changes that enable constitutive, ligand-independent, activation of the KIT protein. Oncogenic KIT activation leads to phosphorylation of various substrate proteins and, in turn, to activation of signal transduction cascades regulating cell proliferation, apoptosis, chemotaxis, and adhesion. Recently, a small molecule tyrosine kinase inhibitor (STI571, imatinib mesylate, Gleevec) directed against the enzymatic (kinase) domain of the KIT protein was found to produce dramatic clinical responses as monotherapy for metastatic GISTs. This review focuses on the biological and molecular genetic principles of GISTs, and particularly the role of mutant KIT as a therapeutic target.