The interaction between CD40 and CD154 regulates many aspects of cellular and humoral immunity. The CD40-CD154 pathway is important for resistance against a variety of parasites. Studies done with these pathogens have provided important insight into the various mechanisms by which this pathway enhances host protection, mechanisms by which pathogens subvert CD40 signaling, conditions in which the CD40-CD154 pathway promotes disease and on modulation of this pathway for immunotherapy.