CAR T cell therapies are generally optimized for short-term cellular responses and may not allow for long-term systemic eradication of the tumor. To enable precise control of CAR T cell function over time, a first solution has been developed. Researchers have exploited recently developed synthetic Notch receptors to design enhanced CAR T cells with a second receptor. The second receptor can recognize a tumor antigen and then cause the T cell to release the cytokine interleukin-2, but when the CAR T cells are in direct contact with the tumor cells. In a mouse model, the approach enabled CAR T infiltration of solid pancreatic and melanoma tumors, resulting in substantial tumor eradication. In addition, a second solution was developed. Researchers developed a toolbox of 11 programmable synthetic transcription factors that could be activated on demand with timed administration of FDA-approved small-molecule inducers. Using these tools, the authors designed human immune cells that activate proliferation and antitumor activity on demand. The combination of the two technological advances presented will provide an unprecedented ability to precisely control the state of therapeutic cell populations not only at the time of injection but also as the immune response unfolds in the patient.