Abstract: Whereas most gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT or PDGFRA mutations, a subset has genetic or epigenetic alterations leading to loss of function of the succinate dehydrogenase (SDH) complex. These SDH-deficient GISTs have a distinct clinicopathologic profile: gastric location, occurrence at an early age, predominance in females, often indolent course, and long survival with liver metastases. Carney triad and Carney-Stratakis syndrome–associated GISTs belong to SDH-deficient GISTs. Some patients have other SDH deficiency–associated tumors: paragangliomas and renal cell carcinomas. Histologically, SDH-deficient GISTs are typically composed of multiple tumor islands of epithelioid tumor cells spaced by muscularis propria elements. Lymphovascular invasion and lymph node metastases occur almost exclusively in these GISTs. Immunohistochemically diagnostic is loss of SDHB in tumor cells in all cases, whereas loss of SDHA is specific to examples with loss of SDHA. Similar to KIT-mutant GISTs, SDH-deficient GISTs also strongly express KIT and DOG1/Ano-1 and usually also CD34, but these GISTs do not have KIT or PDGFRA mutations. Their genetic basis includes loss of function in SDH subunit genes (most commonly SDHA) and possibly epigenetic silencing, and genomic methylation is a typical feature of SDH-deficient GISTs. Succinate dehydrogenase–deficient GISTs should be specifically recognized, as these tumors may not respond to the standard KIT tyrosine kinase inhibitors, such as imatinib mesylate, in contrast to KIT-mutant GISTs.