Historically, patients with inoperable gastrointestinal stromal tumors (GISTs) had a very poor prognosis because of the highly resistant nature of these tumors to conventional chemotherapy. The rational and progressive development of tyrosine kinase inhibitors (TKIs) since the initial proof-of-concept studies with imatinib mesylate in the late 1990s, all designed to exploit key pathways that lead to GISTs being so oncogenically addicted, have revolutionized the treatment of GIST. Median overall survival has improved from less than a year to at least 5 years in patients with advanced or metastatic disease. Imatinib remains the standard first-line treatment in advanced GIST; however, resistance to imatinib and subsequent other TKIs inevitably develops in most but not all patients. As much as efforts will continue to identify new drugs for patients with disease that becomes refractory to these agents, there has also been a need to focus on optimizing the use of currently available therapies by using a combination of molecular tools to stratify patients more effectively, pharmacodynamic markers and pharmacokinetic modeling to maximize these agents' activity in individual patients, and reappraising the role of surgery in the management of patients with metastatic disease. These all form part of a modern, multidisciplinary approach to the management of GIST patients.