The first studies of mice deficient in lymphotoxin-α (LTα), LTβ and LTβR revealed the seminal discovery that the LTβR signaling is critical for the development of lymph nodes and Peyer's patches during embryogenesis. Since these initial findings, it is increasingly appreciated that signaling through the lymphotoxin-β receptor (LTβR) plays a key role in numerous biological processes in the adult animal, including the maintenance of specialized stromal cell types and the homeostatic control of chemokine expression within the lymphoid tissues. A major focus of our laboratory is to understand the relevance of LTβR signaling in initiating immune responses both dependent and independent of its role in maintaining the organization of lymphoid tissues. This review will therefore explore new possibilities for how this complex pathway regulates humoral and cellular immunity.