<p>Chimeric antigen receptor (CAR) T-cell therapy, long established in the treatment of hematologic cancers, is now drawing significant interest as a transformative strategy for autoimmune and infectious diseases. Early in the preclinical sphere, and at an even greater pace in the clinic, the first-of-their-kind CARs that express anti-inflammatory cytokines have demonstrated prolonged long-term remission in patients with recalcitrant autoimmune conditions, including systemic lupus erythematosus and rheumatoid arthritis. Concurrently, there are studies to adapt CAR T cell technology to chronic viral infections such as HIV by targeting viral latency and immune-mediated clearance. The accuracy and cytotoxic potential of engineered T cells for specific eradication of pathogenic immune cells or infected targets is exploited by these applications. Yet, hurdles remain, including the potential for cytokine release syndrome and immune-related toxicities, as well as the development of scalable, off-the-shelf CAR T-cell products. In this review, we lay the groundwork for the non-oncologic design with essential CAR-T cell concepts, apply these principles to emerging autoimmunity and infectious disease CAR targets, and explore the most recent advances in synthetic biology, safety, and biomarker-directed strategies to push the boundaries of personalized cellular immunotherapy.</p>