Treatment of gastrointestinal stromal tumor (GIST) is a paradigm for targeted therapy. These mesenchymal tumors are refractory to standard chemotherapy and radiation therapy. Targeted therapy has successfully exploited the oncologic drivers of GIST--the tyrosine kinases, KIT, and the platelet-derived growth factor receptor. Therapy with imatinib has dramatically altered the natural history of patients with advanced GIST. However, patients are developing resistance to imatinib and thus presenting with a major clinical challenge. Alternative approaches to imatinib-refractory disease are needed. Newer approaches using biologic data regarding the mechanisms of resistance are being tested alone or in combination with imatinib and are the focus of this review. Effective novel agents for imatinib-refractory GIST used as single agents or in combination with imatinib will likely become future regimens to be tested in first-line metastatic disease and in the adjuvant setting.