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Summary Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes., Graphical Abstract, Highlights • Inhibitors of LSD1 target both scaffolding and enzymatic functions of the protein • GFI1/CoREST complex is targeted for disruption and release from chromatin • GFI1/CoREST disruption is required for leukemia cell differentiation • Loss of enhancer-bound GFI1/LSD1 activates nearby myeloid differentiation genes, Maiques-Diaz et al. report that, while LSD1 inhibitors target both scaffolding and enzymatic functions of the protein, drug-induced myeloid leukemia cell differentiation is primarily due to the disruption and release from enhancers of GFI1/CoREST complexes, leading to the activation of subordinate myeloid transcription factor genes.