The development of Chimeric Antigen Receptor (CAR) T-cell therapy represents a transformative advancement in cancer immunotherapy. Initially conceptualized in the early 1980s, CAR T-cell therapy emerged from efforts to engineer T cells to recognize and target tumor-specific antigens. This therapy involves the genetic modification of autologous T cells to express synthetic receptors (CARs) that target tumor antigens independently of major histocompatibility complex (MHC) presentation, providing a highly specific and personalized treatment modality. CAR-T-cell therapy has demonstrated significant success, particularly in the treatment of relapsed or refractory hematological malignancies. Despite its revolutionary impact, CAR-T therapy faces several challenges, including antigen escape, treatment-related toxicities such as cytokine release syndrome (CRS) and neurotoxicity, and limited efficacy in solid tumors. Over the years, the field has advanced with innovations in CAR design, manufacturing processes, and combinatorial therapeutic approaches. These advancements have broadened the clinical applications of CAR-T-cell therapy, and ongoing research holds promise for overcoming current limitations and enhancing therapeutic outcomes across a wider range of cancers. This chapter provides an overview of the fundamental principles underlying CAR design, recent innovations in CAR-T technologies, and the clinical translation of CAR-T-cell therapy.