Systems biology approaches, including computational models, provide a framework to test biological hypotheses and optimize effective therapeutic strategies to treat human diseases. In this talk, I present recent work in modeling signaling in cancer-targeting immune cells, with a focus on CAR T cells. Chimeric antigen receptors (CARs) are comprised of a variety of different activating domains and co-stimulatory domains that initiate signaling required for T cell activation. However, there is a lack of understanding of the mechanisms by which activation occurs. We aim to fill this knowledge gap by applying mathematical modeling to investigate how CAR structure influences downstream T cell signaling and develop new hypotheses for the optimal design of CAR-engineered T cell systems. Our work addresses questions regarding the role of signaling domains and kinase activity in the activation of engineered T cells and can be used to guide CAR T cell design.