Abstract Cancer immunotherapy has reshaped the landscape of cancer treatment over the past decades. Genetic manipulation of T cells to express synthetic receptors, known as chimeric antigen receptors (CAR), has led to the creation of tremendous commercial and therapeutic success for the treatment of certain hematologic malignancies. However, since the engagement of CAR-T cells with their respective antigens is solely what triggers their cytotoxic reactions against target cells, the slightest changes to the availability and/or structure of the target antigen often result in the incapacitation of CAR-T cells to enforce tumoricidal responses. This results in the resistance of tumor cells to a particular CAR-T cell therapy that requires meticulous heeding to sustain remissions in cancer patients. In this review, we highlight the antigen-dependent resistance mechanisms by which tumor cells dodge being recognized and targeted by CAR-T cells. Moreover, since substituting the target antigen is the most potent strategy for overcoming antigen-dependent disease relapse, we tend to highlight the current status of some target antigens that might be considered suitable alternatives to the currently available antigens in various cancers. We also propose target antigens whose targeting might reduce the off-tumor adverse events of CAR-T cells in certain malignancies.