Molecularly targeted agents have dramatically impacted the management of several cancers. Targeting KIT has led to a new treatment paradigm in gastrointestinal stromal tumors (GISTs). KIT is a cell surface receptor with tyrosine kinases that, upon binding of its ligand, stem cell factor, activates various signaling pathways. Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for first- and second-line treatment of metastatic and unresectable GISTs. In this article, we will review the molecular pathogenesis of GISTs followed by a discussion of imatinib and sunitinib's role in the treatment of GISTs. Finally, we will introduce novel therapeutic options for imatinib- and sunitinib-resistant GISTs.