The literature on gastrointestinal stromal tumors (GISTs) has rapidly expanded and has demonstrated how scientific advancements in diagnosis can revolutionize the understanding of disease, while paving the way for effective treatment. While KIT (CD117) immunohistochemistry has established our definition of GISTs, molecular genetics continue to refine it. Elucidation of the aberrant receptor tyrosine kinase (RTK) model of GIST pathogenesis through mutations in c-kit and platelet-derived growth factor alpha PDGFRalpha proto-oncogenes has been prerequisite to the use of imatinib mesylate (STI571, Gleevec; Novartis, Switzerland), a molecular inhibitor of several tyrosine kinases, in the treatment of GISTs. In addition to providing a means for effective treatment, clarification of the molecular pathology of GISTs may potentially offer a new classification of these tumors by correlating genotype with histological, immunohistochemical, and clinical phenotype. This article seeks to review current knowledge of GISTs, offering a practical guide to their diagnosis and describing current epidemiological, molecular biological, and therapeutic aspects.