In recent years, immunohistochemical staining for KIT (CD117) has become integral to the diagnosis of gastrointestinal stromal tumors (GISTs), nearly 90% of which harbor activating mutations in the KIT receptor tyrosine kinase gene. Approximately 80% of patients with metastatic GIST show at least some clinical response to the targeted small molecule KIT inhibitor imatinib. The response to imatinib is closely correlated with the presence and type of KIT mutation. GISTs with the most common KIT exon 11 mutations have the highest response rate by far, whereas GISTs lacking mutations in KIT or the alternative receptor tyrosine kinase PDGFRA show much lower rates of response to imatinib. Less than 5% of GISTs are KIT-immunonegative; and many of these tumors have activating mutations of PDGFRA, some of which are also inhibited by imatinib. Most patients who initially respond to imatinib become resistant and eventually progress, which coincides with the selection of imatinib-resistant secondary KIT mutations in the kinase domain. Sunitinib has recently been approved for patients with GIST, principally those who fail imatinib therapy; and additional small molecule inhibitors are in the pipeline. It is becoming evident that alternative approaches to direct KIT inhibition will be required for long-term survival of patients with advanced GISTs. This review examines the role of KIT in the diagnosis and management of patients with GIST.