Chimeric antigen receptor (CAR)-engineered T cells can mediate impressive responses in a subset of patients with B cell malignancies. Clinical trial and real-world data, however, reveal that most patients will not achieve durable remission. Therapeutic failure appears to segregate into two distinct models: inherent resistance, in which there is no meaningful disease response after treatment, or acquired resistance, in which disease recurrence follows a transient response. A host of studies have identified that both forms of failure can result from tumor-intrinsic evasion mechanisms which can be antigen-dependent or independent. Alternatively, resistance or relapse can occur due to T cell dysfunction, both intrinsic to the cells prior to infusion or that develops after delivery to patients. In this chapter, we review the mechanistic and correlative studies investigating resistance to CAR-T cells, and discuss strategies designed to overcome this significant hurdle to the broader success of this therapy.