<p>Chimeric antigen receptor (CAR) T cell therapy is a ‘living drug’ in which the T cells of patients are genetically engineered with an artificial receptor that directs them to attack diseased cells. CAR T cell therapies have had remarkable impact, curing subsets of patients with previously untreatable, late-stage cancers. However, limitations persist, including severe toxicities, limited survival of engineered cells, and therapeutic resistance. Genetically encoded small-molecule control systems have been developed to address these limitations. They can halt toxicities by eliminating CAR T cells or switching off their function. Furthermore, they can enhance therapy by directly targeting antigens or broadening cell killing ability through cytotoxic pro-drug activation. Small-molecule controllers include protease inhibitors, protein dimerizers, protein degraders, bi-specific adaptors and conditionally activated chemotherapeutics. Here, we outline small-molecule-based control approaches, categorizing them by function and detailing their molecular mechanisms. We emphasize systems in the clinic and highlight emerging applications and unmet areas.</p><p></p>