Chimeric antigen receptor (CAR)-T and -NK cells showed great success in treating hematological malignancies, including leukemia, lymphoma, and myeloma. CRISPR technology and other synthetic receptors (GPCR and synNotch) have helped to address some of the limitations and challenges associated with CAR-based therapies. Herein, this review aims to discuss how CAR can be integrated with other synthetic receptors and various CRISPR/Cas tools for blood cancer therapy. CAR-expressing cells equipped with other synthetic receptors can conditionally execute tumoricidal functions, prevent tumor escape from immune surveillance, and minimize non-tumor off-target toxicity. We also discussed how various CRISPR-Cas tools can be harnessed to enhance CAR cells functionality and persistence. The advances, pitfalls, and future perspectives for these synthetic receptors and CRISPR technology in blood cancer therapy are comprehensively discussed.