Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract. Traditionally, surgery has been the primary treatment modality for these tumors, with only modest results. The recent development of kinase inhibitors (most notably, imatinib mesylate) has provided a new paradigm for the treatment of this disease. Response rates approaching 60% have been seen in studies in patients with advanced disease. Previously, chemotherapy played little role in the treatment of this disease. Now, however, treatment with kinase inhibitors can increase the number of patients who may potentially benefit from surgical intervention. Many questions regarding the use of kinase inhibitors remain. Most importantly, the optimal duration of treatment before surgical intervention and following both complete and incomplete tumor resection remains to be elucidated. Ongoing prospective trials have the potential to provide some of these answers in the near future.