INTRODUCTION: A subset of gastrointestinal stromal tumors (GISTs) lacks the common mutations in AREAS COVERED: In this manscript, we review the pathogenesis, natural history, diagnostic features and management of EXPERT OPINION: Patients should be managed in reference centers. There has been progress in the understanding of the biology of these GISTs, and promising therapeutic targets have been identified. In SDH-deficient GISTs, the TKI olverembatinib has shown encouraging clinical activity but requires further clinical validation, while the HIF2a inhibitor bezultifan and temozolomide alone or in combination with the death receptor agonist 5 are under clinical investigation. Targeting the RAS/RAF pathway in RAS/RAF-mutated GISTs warrants evaluation in clinical trials. Rare molecular alterations in quadruple WT GISTs require investigation for their oncogenic potential. Collaborative research and patient advocacy is critical for these extremely rare tumors.