Chimeric antigen receptor T (CAR T) cell therapy is a new treatment paradigm that has revolutionized the treatment of CD19-positive B cell malignancies and BCMA-positive plasma cell malignancies. The response rates are highly impressive in comparison to historical cohorts, but the responses are not durable. The most recent results from pivotal trials show that current CAR T cell products fail to demonstrate optimal long-term disease control. Resistance to CAR T cells is related to CAR structure, T cell factors, tumor factors and the immunosuppressive microenvironment. Novel strategies are needed following failure with CAR T cell treatment. In this review, we discuss the resistance mechanisms to CAR T cell treatment according to disease and the emerging strategies to overcome resistance.