Imatinib mesylate has revolutionized the treatment of GIST. Dramatic changes in clinical practice have been observed in the past decade. Nonetheless, time has also revealed the limitations of treating GIST with a single agent alone, as resistance to imatinib has become a significant clinical dilemma. Surgical resection still remains the only chance for a cure. However, it is clear that GIST is a complex disease and requires effective integration of surgery and targeted therapy to reduce recurrence after resection of primary GIST or to prolong survival in metastatic disease. Recent studies have begun to delineate the feasibility of multimodal treatment of this disease. Knowledge gained thus far, along with ongoing and future investigations of GIST, will be extremely relevant to the potential use of molecular targeted therapy for other solid neoplasms.