The regulation of the immune system at the cell surface is primarily controlled by two families of cosignaling molecules: the immunoglobulin (Ig) superfamily, or CD28 and B7 family, and the tumor necrosis factor receptor (TNFR) family. Here, we summarized the principal structural and functional characteristics of both families. In this respect, the interaction between HVEM, a TNF receptor, and BTLA, an Ig family member, has provided a new perspective and an additional level of complexity in the crosstalk between these two regulatory systems. This review will present a summary of the recent advances in the immunobiology of the LIGHT-HVEM-LTβR-BTLA network. The LIGHT-HVEM-BTLA system has emerged as a major regulator of immune responses and lymphocyte activation, whereas LIGHT-LTβR participates in lymphoid tissue development and cell death. Moreover, recent studies have provided encouraging new insights into the roles of the LIGHT-HVEM-LTβR-BTLA axis as a potential target for controlling anti-tumor responses.