Significance Enhancers are regulatory regions in DNA that govern gene expression and orchestrate cellular phenotype. We describe the enhancer landscape of gastrointestinal stromal tumor (GIST), identifying established and unique GIST-associated genes that characterize this neoplasm. Focusing on transcriptional regulators, we identify a core group of transcription factors underlying GIST biology. Two transcription factors, BARX1 and HAND1, have mutually exclusive enhancers and expression in localized and metastatic GIST, respectively. HAND1 is necessary to sustain GIST proliferation and KIT expression, and binds to enhancers of GIST-associated genes. The relative expression of BARX1 and HAND1 is predictive of clinical behavior in GIST patients. These results expand our understanding of gene regulation in this disease and identify biomarkers that may be helpful in diagnosis and treatment.