Coordination of immune cell metabolism (immunometabolism) with cell fate and state is a fundamental determinant of immune responses. As metabolic pathways are inextricably connected to immunity and cancer, understanding these connections allows us to gain new insights into immunological concepts and disease targets. In particular, immunometabolism has key roles in shaping the functional fitness of both regulatory and effector T cells in the tumor microenvironment. Here I will discuss our recent findings regarding how mTOR and other signaling pathways bridge nutrient signals and cell metabolic programs to direct T cell priming and function, and the implications in immune tolerance and antitumor immunity. I will also discuss the use of systems immunology and functional genomics approaches including pooled CRISPR screening to investigate metabolic signaling and identify new therapeutic targets for cancer and immune-mediated diseases.