TNF-related ligands (with the exception of lymphotoxin-α) are synthesized as type II transmembrane proteins, though many of them also have soluble forms. An increasing number of publications report that these ‘ligands’ behave as receptors, activating intracellular signaling pathways when interacting with cognate ‘receptors’ or agonistic antibodies. Most members of the TNF family and their receptors influence survival, proliferation, differentiation or activation of immune cells. The elicited ‘reverse signals’ also have significant importance. They proved to be involved in the activation of APCs, T and B cells, differentiation of osteoclasts and apoptosis of activated macrophages. They influence the balance between destructive immune response and tolerance. Several examples show that therapeutic manipulation of the reverse signal can help to treat malignancies as well as autoimmune disorders.