Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in Oncology. Most GISTs are KIT-expressing and KIT-signaling driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding for a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light onto the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; and activating KIT mutations have been identified in tumors affecting most of these cell lineages. The observation that KIT mutations may be inherited, as seen in familial GIST syndrome, was used to develop murine models harboring a germline gain-of-function mutation, as a model for studying of KIT oncogenic mechanisms. These murine models of human GIST promise to become powerful preclinical tools in elucidating oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention. As true animal models of human cancer, they provide superior information compared with the more commonly used xenografts and transgenic mouse models. This review summarizes the recent knowledge on the central role of KIT oncogenic activation and subsequent signal transduction in the pathogenesis of GIST. In addition, we provide an updated discussion on familial GIST syndrome in relationship to genotype-phenotype characteristics. A succinct description of the available murine models of human GIST is presented and their applicability in further understanding of the KIT oncogenic signaling, drug screening, and mechanisms of drug resistance is discussed. This is a US government work. There are no restrictions on its use.