The treatment of gastrointestinal stromal tumors (GISTs) has been a model for targeted cancer therapy. The discovery of driver somatic mutations in the KIT and PDGFRA receptor tyrosine kinases led to a shift of therapy from conventional cytotoxic chemotherapy to inhibitors of these receptors. Targeted molecular therapy of GIST has markedly increased the overall survival of patients with advanced disease. However, the ability of kinase therapy to control metastatic disease is ultimately limited by the ability of these agents to overcome intrinsic or acquired resistance mechanisms. Ongoing basic and clinical research is focusing on identifying new agents to inhibit KIT/PDGFRA kinase activity and/or other novel molecular targets in GIST.