Gastrointestinal stromal tumor (GIST) is a well-recognized and now relatively well-understood mesenchymal tumor. Before the imatinib era, the treatment of metastatic GIST was frustrating owing to its refractoriness to conventional chemotherapy and radiotherapy. After a metastatic GIST patient was granted compassionate use of imatinib in 2000, the treatment of this disease has emerged as a model for the development of other molecularly targeted therapies. In this article the authors review how tumor genotypes, in particular KIT and PDGFRA mutational analysis, have been integrated in the optimal clinical management of GIST patients. The authors also discuss the potential practical relevance of pharmacogenetics, which, integrated with therapeutic drug monitoring, should receive greater consideration, with the aim of personalized therapy.