Chimeric Antigen Receptor (CAR) T-cell therapy has profoundly impacted cancer immunotherapy by providing a means for autologous T lymphocytes to be genetically engineered and programmed to recognize and kill tumor cells without MHC restriction. CAR T-cell therapy was first shown to be effective in patients with hematological malignancies. Now, as we sit on the cusp of the next stage of precision oncology, CAR T-cell therapy has the potential to emerge as a transformative approach for patients with malignant relapse or refractory disease. This chapter will provide a complete historical and scientific overview of CAR T-cell therapy, from the initial theoretical concepts of adaptive biology to important advances in molecular biology, T-cell construct engineering, and clinical practice. We review the evolving structural nature of CAR design from first- to fourth-generation models, highlight significant challenges associated with their application in solid tumors, and explore solutions attempting to mitigate these challenges, such as armored CAR constructs, logic-gated platforms, and engineered chemokine receptors. We will also discuss the future trajectory of CAR T-cell therapy, including universal off-the-shelf products, therapeutic use outside the field of oncology, the use of artificial intelligence and synthetic biology, and the future possibilities of CAR T-cell therapy. Collectively, this chapter serves as a comprehensive overview of how CAR T-cell therapy has transformed from a revolutionary concept to the development of a rapidly expanding platform for next-generation cellular medicine.