ABSTRACT Autoimmunity causes damage to organs targeted by the effector function of the immune response. The dynamics of autoimmunity in human peripheral tissues are not well understood due to the limited access to tissue samples. As cellular metabolism controls immune function, studying the crosstalk between the environment and cells within a tissue may provide information on how the metabolism of immune cells drives autoimmunity in peripheral tissues. In this review, I discuss some of the work that explored the complexity of the tissue environment, its sensing by cells in the tissue, and the consequences this has on cell and tissue functions, highlighting implications for autoimmune diseases. I also suggest a framework to study immunometabolism in tissues, contextualizing the metabolic choices of immune cells within the diversity of the extracellular environment they encounter.