Improvements in the understanding of molecular oncogenesis and mechanisms of drug resistance have presented new opportunities for the treatment of gastrointestinal stromal tumors (GIST). In particular, the discovery of c-kit genomic mutations in GIST and the development of targeted therapy with imatinib mesylate and sunitinib have heralded a new era in the treatment of this disease. Due to its high activity in GIST, imatinib has become the standard of care in treating both advanced disease and localized disease with high-risk features. On the other hand, these developments have provided new challenges in optimizing the use of our drug armamentarium in conjunction with surgery. This review focuses on the molecular oncogenesis of GIST and provides a summary of recent approaches in the management of this disease.  (More)