The tumor microenvironment (TME) is an intricate network of cells around the tumors that nourishes tumor cells’ growth and provides a safer environment to help tumor cells evade immune surveillance. In the TME, the pervasiveness of physical barriers, immunosuppressive factors, metabolic environment, tumor heterogeneity, inflammation, and immune evasion are the major factors that hinder anticancer therapy. In chimeric antigen receptor (CAR) T-cell therapy, T cells are designed by introducing a pre-synthesized receptor that combines an extracellular antigen-recognition domain with intracellular signaling domains, enabling the T-cells to recognize and eliminate cancer cells in a major histocompatibility complex (MHC)-independent way. The success of CAR T-cell therapy is higher in hematologic malignancies than in solid tumors, due to the prevalence of strong TME in solid tumors, which inhibits the penetration of CAR T-cells into the tumor cells. Also, cytokine release syndrome and immune suppression are significant challenges in hematologic malignancies. To conquer these obstacles, next-generation CAR T-cell therapies are being engineered to interrupt the TME barrier and overcome the immunosuppressive environment to target CART cells effectively. This chapter will shed light on the challenges of CAR T-cell therapy in targeting the tumor microenvironment of solid and hematologic malignancies. In addition, strategies to optimize the CART treatment and the preclinical and clinical development of CART therapies to successfully target the TME of hematologic and solid malignancies will be comprehensively discussed.