The clinical application of tyrosine kinase inhibitors for cancer treatment represents a therapeutic breakthrough. The rationale for development of these compounds rests on the observation that tyrosine kinases are central components of the cellular signaling apparatus and are deregulated in many human malignancies. Successful tyrosine kinase inhibitors target aberrant pathways that are critical for tumor cell viability. Herein, we will review the current state-of-the-art using imatinib mesylate (Gleevec™, Glivec®, CGP57148, formerly STI571; Novartis Pharmaceuticals) as it is used in the treatment of gastrointestinal stromal tumors (GISTs). GISTs, the most common mesenchymal tumors of the gastrointestinal tract, originate from the neoplastic transformation of the intestinal pacemaker cell, the interstitial cell of Cajal. GISTs commonly have mutations in the kit gene, resulting in a gain-of-function mutation and ligand-independent constitutive activation of the Kit receptor tyrosine kinase. The use of imatinib has greatly increased the therapeutic efficacy for this otherwise chemotherapy-resistant tumor. Resistance to the drug is the major cause of treatment failure, emphasizing the need for researchers to understand Kit signaling pathways so as to identify new therapeutic targets. This article will review the development, pharmacology, and clinical trials of imatinib in the setting of GIST. The potential role of imatinib in the postoperative and preoperative setting will be discussed.