The LIGHT-related molecular network is composed of at least seven interacting receptors and ligands. Recent studies reveal that this network has profound immune regulatory functions for both innate and adaptive immunity. Experimental data support the concept that this network may also play roles in the pathogenesis of human diseases including cancer, infection, transplantation tolerance, and autoimmune diseases. In this review, we attempt to dissect each molecular interaction in detail and assemble them in the context of their roles in the pathogenesis and possible therapeutic potential in human diseases.