Adoptive transfer of tumor-reactive T cells into cancer patients with the intent of inducing a cytotoxic anti-tumor effector response and durable immunity has long been proposed as a novel therapy for a broad range of malignancies; however, local and systemic tolerance mechanisms have hindered the generation of effective T cell therapies and limited the clinical efficacy of this approach in cancer patients. Chimeric antigen receptors (CARs) are recombinant receptors that comprise an extracellular antigen-targeting domain in conjunction with one or more intracellular T cell signaling domains that can be introduced into T cells by genetic modification to redirect their specificity to the CAR-targeted antigen. Administration of CD19-specific CAR-modified T cells that target B cell non-Hodgkin lymphomas and leukemia has been remarkably effective in recent clinical trials, energizing the field and stimulating new efforts to identify the critical parameters of CAR design and T cell engineering that are necessary for effective cancer therapy.