Although chimeric antigen receptor (CAR) T cell therapy (CAR-T) has altered the treatment landscape for relapsed/refractory B cell malignancies and multiple myeloma, only a minority of patients attain long-term disease remission. The underlying reasons for CAR-T resistance are multifaceted and can be broadly divided into host-related, tumor-intrinsic, microenvironmental and macroenvironmental, and CAR-T-related factors. Emerging host-related determinants of response to CAR-T relate to gut microbiome composition, intact hematopoietic function, body composition, and physical reserve. Emerging tumor-intrinsic resistance mechanisms include complex genomic alterations and mutations to immunomodulatory genes. Furthermore, the extent of systemic inflammation prior to CAR-T is a potent biomarker of response and reflects a proinflammatory tumor micromilieu characterized by infiltration of myeloid-derived suppressor cells and regulatory T cell populations. The tumor and its surrounding micromilieu also can shape the response of the host to CAR-T infusion and the subsequent expansion and persistence of CAR T cells, a prerequisite for efficient eradication of tumor cells. Here, focusing on both large B cell lymphoma and multiple myeloma, we review resistance mechanisms, explore therapeutic avenues to overcome resistance to CAR-T, and discuss the management of patients who relapse after CAR-T.