Gastrointestinal stromal tumors (GISTs) are rare soft tissue sarcomas of the gastrointestinal tract, with most carrying conserved driver mutations in the tyrosine kinase receptors KIT or PDGFRα. The use of targeted therapy against these mutations in GISTs is one of the most successful examples of precision medicine in solid tumors, beginning in 2002 with the development of imatinib, a small molecule tyrosine kinase inhibitor (TKI) of KIT. In recent years, much progress has been made in understanding the molecular mechanisms of GISTs while unveiling their genetic heterogeneity. Since development of secondary mutations leads to imatinib resistance, the majority of research efforts have focused on identification of novel inhibitors to improve outcomes in imatinib-resistant GISTs. Sunitinib and regorafenib are two TKIs with demonstrated activity after failure of imatinib, which led to the U.S. FDA approval. Pivotal phase 3 clinical trials are ongoing with two novel agents, avapritinib and ripretinib, based on their remarkable activities in the 4th or greater line settings in phase 1/2 studies of these drugs. In this review, we will outline the remarkable diversity of genetic mutations in GISTs, and review the evidence for treatment options of genomic medicine in locally advanced or metastatic gastrointestinal stromal tumors.