Gastrointestinal stromal tumors (GISTs) are identified pathologically by the expression of KIT. The management of GISTs has been altered significantly by the development of imatinib mesylate, a tyrosine kinase inhibitor with activity against KIT and platelet-derived growth factor receptors. This article reviews the management of GISTs in the era of molecular therapies. The role of surgery alone or in combination with imatinib in the adjuvant and metastatic setting is discussed. GISTs resistant to imatinib are becoming a clinical challenge; this article discusses novel therapies under development.