A gastrointestinal stromal tumor (GIST) is a rare mesenchymal malignancy of the gastrointestinal (GI) tract. Malignant GISTs were first defined as a separate entity from a collection of nonepithelial malignancies of the GI tract in the 1980s and 1990s based on pathologic and clinical behavior. The discovery of activating KIT mutations as a near-uniform occurrence in these tumors greatly influenced the classification [1] and revolutionized therapeutic management of these tumors. To meet the next challenges, newer tyrosine kinase inhibitors and targeted agents are being developed with the goal of providing improved response rates or alternative therapies for patients progressing on established agents. In this article, the authors describe the management of GISTs, concentrating on surgical management and targeted therapies.