Targeted therapies – small molecules designed to inhibit activated oncogenes – have revolutionized cancer treatment. However, despite patients frequently gaining benefit from these drugs, cancer cells invariably become resistant leading to tumour relapse. In addition to resistance due to pre-existing secondary mutations, acquired resistance can occur via other mechanisms and often follows a drug-tolerant state. The small fraction of cells that consistently survives targeted therapy, so-called drug-tolerant persisters (DTPs), are slow-cycling and share characteristics with cancer stem cells. These cells provide a reservoir from which genetic resistance can emerge. We have identified a number of noncoding RNAs that contribute to DTP biology, some of which represent vulnerabilities with the potential to improve responses to targeted therapy.