Gastrointestinal stromal tumors are rare mesenchymal tumors of the gastrointestinal tract. Progress in diagnosis has led to increased recognition of this disease, and the availability of effective, molecularly targeted therapy has revolutionised its management. Treatment of metastatic gastrointestinal stromal tumors with imatinib has led to unprecedented improvements in progression free and overall survival and there are ongoing investigations into the optimal pre-operative and adjuvant use of imatinib. Second-line sunitinib is now available for patients who develop resistance to imatinib, and third- and fourth-line therapies are being investigated in clinical trials. In this ever-changing environment, evidence from controlled clinical trials and the authors' experience were used to comprehensively outline current best practice management of patients with gastrointestinal stromal tumors.