Chimeric antigen receptor T-cell therapy, also known as CAR T-cell therapy, is the ex vivo engineering of T cells with receptors containing stimulatory and signaling domains that bind to T-cell receptors on CD8+ T cells, inducing cytotoxicity in tumor cells. First-, second-, third-, and fourth-generation CAR T cells have been designed and constructed for improved efficacy and favorable safety profiles. The JULIET and ZUMA trials evaluated CAR T-cell therapies tisagenlecleucel and axicabtagene ciloleucel for pediatric hematologic malignancies with poor prognosis, such as large B-cell lymphoma (LBCL), and they were met with extraordinary efficacy, receiving approval with breakthrough therapy designation. This chapter describes newer-line therapies for mantle cell lymphoma, multiple myeloma, and solid tumors to counter the challenges posed by an immunosuppressive tumor microenvironment, target antigen heterogeneity, and managing cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).