Adaptive immune responses mediated by T cells and B cells are crucial for protective immunity against pathogens and tumors. Differentiation and function of immune cells require dynamic reprogramming of cellular metabolism. Metabolic inputs, pathways, and enzymes display remarkable flexibility and heterogeneity, especially in vivo. How metabolic plasticity and adaptation dictate functional specialization of immune cells is fundamental to our understanding and therapeutic modulation of the immune system. Extensive progress has been made in characterizing the effects of metabolic networks on immune cell fate and function in discrete microenvironments or immunological contexts. In this review, we summarize how rewiring of cellular metabolism determines the outcome of adaptive immunity in vivo, with a focus on how metabolites, nutrients, and driver genes in immunometabolism instruct cellular programming and immune responses during infection, inflammation, and cancer in mice and humans. Understanding context-dependent metabolic remodeling will manifest legitimate opportunities for therapeutic intervention of human disease.