The T cell co-signaling pathways within the B7-CD28 family are crucial for the regulation of activation and tolerance of T cell immunity. These pathways not only provide critical positive second signals that initiate, augment and sustain T cell responses, but also contribute key negative signals that limit, terminate and/or attenuate T cell responses. Appropriate manipulation of these co-signaling pathways may promote immune responses against viral infection and cancer, and reduce graft rejection and autoimmune diseases (1). In the past five years, much excitement has been centered in rapid identification of novel pathways and characterization of their functions. The B7-CD28 family is rapidly expending in recent years (Figure 1). This review will focus on discussion and synthesis of newly discovered pathways including B7-H1/B7-DC/PD-1, B7-H2/ICOS, B7-H3, B7-H4 and BTLA, as well as their functional implications in the context of pathogenesis and potential applications for the treatment of human diseases.