Therapeutic failure remains a common problem in cancer treatment. Our lab has developed induced drug-tolerant cells (IDTCs) modelling the non-genetic and reversible acquisition of drug resistance in tumour cells following treatment. We recently showed that IDTCs derived from melanoma, lung, breast, liver and colorectal cancer cell lines underwent similar cellular reprogramming under treatment that was associated with significant and consistent increases in the epigenetic modifiers SETDB1 and SETDB2. Here we show that SETDB1 and SETDB2 are induced by type I IFN signalling that is reactivated following drug exposure in IDTCs, which subsequently promotes heterochromatin formation and transcriptional rewiring via HP1-mediated propagation of H3K9me3. ChIP-seq revealed SETDB1/2-mediated repression of key cell cycle and pro-apoptotic genes such as CCND1 and BID, and knockdown of SETDB1/2 partially rescues their expression. Knockdown of SETDB1/2 had minor effects on IDTC proliferation, senescence features, colony formation and showed prolonged responses to high dose/ multidrug treatment over 6d. We also investigated H3K9me3 redundancy in IDTCs and identified that SETDB1/2 knockdown leads to upregulation of other compensatory methyltransferases. This work aims to elucidate details of this acquired resistance mechanism in order to improve the efficacy and length of cancer therapies through the suppression or prevention of tumour relapse.