CD40 is recognized as a member of tumor necrosis factor receptor super family. It is expressed by the immune and non-immune cells. Its interaction with CD40 ligand (CD154) brings about a regulatory effect on the cellular and humoral immunity. The pathway of CD40-CD154 is influential in various diseases. Investigations on such diseases have revealed dimensional mechanisms whereby this route intensifies host protection. Moreover, through these mechanisms, pathogens subvert the signaling of the CD40, conditions in which the CD40-CD154 pathway promotes disease and also through the relevant modulation for immunotherapy. This review focuses on the role of CD40-CD40L (CD154) interactions in dendritic cells (DCs) regulation, tolerogenic dendritic cells, role of CD40 in autoimmune disease, allograft rejection and induction of tolerance by down regulation of CD40. According to these roles, it is assumed that CD40 is a functional molecule in the pathologies of conditions like autoimmune diseases and allograft rejection caused by activated T and B cells.