Upon stimulation, lymphocytes develop from small resting cells into highly proliferative and secretory cells. Although a great deal of study has focused on the genetic program induced by Ag receptor signals, lymphocytes must also regulate their metabolic function to meet the energetic demands of activation. In this review, we discuss the changes in cellular metabolism that accompany lymphocyte activation, with a particular emphasis on glucose metabolism, a major source of both energy and biosynthetic building blocks. We will also cover the signaling pathways that positively and negatively regulate these changes to maintain metabolic homeostasis in cells that are rapidly growing, dividing, and differentiating.