We now know that tumor necrosis factor (TNF) family ligands regulate development of lymphoid tissue and coordinate cellular differentiation to defend against intracellular pathogens. In particular, TNF provides essential signals for the formation of secondary lymphoid tissue structures and plays an important role in several physiological and pathological conditions that relate to its action in inflammation and leukocyte movement. The TNF‐related family of membrane‐anchored and secreted ligands also represents a major mechanism regulating cell death and cell survival. TNF was first described as an endotoxin‐induced and macrophage secreted factor that caused haemorrhagic necrosis of tumor cells. Over the past two decades we have come to appreciate that T lymphocytes and natural killer (NK) cells also produce TNF, yet no clear single role for lymphocyte‐derived TNF has emerged. This review describes the key molecular details of the action of TNF and discusses the evidence for TNF‐mediated cytotoxicity being critical to lymphocyte function and immunoregulation. Microsc. Res. Tech. 50:196–208, 2000. © 2000 Wiley‐Liss, Inc.