The identification of activating NOTCH1 mutations in T-cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSI) that prevent NOTCH1 activation1–3. However, responses have been transient4,5, suggesting that resistance limits clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant ‘persister’ cells that expand in the absence of NOTCH signaling. Rare persisters are already present in naïve T-ALL populations, and the reversibility of the phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persisters activate distinct signaling and transcriptional programs, and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 down-regulates these targets and induces growth arrest and apoptosis in persisters, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.