CD40 plays a vital role in humoral immunity, via its potent and multifaceted function as an activating receptor of various immune cells, most notably B lymphocytes. The Epstein‐Barr virus‐encoded transforming protein latent membrane protein 1 (LMP1) serves as a functional mimic of CD40 signals to B cells but lacks key regulatory controls that restrain CD40 signaling. This allows LMP1 to activate B cells in an abnormal manner that can contribute to the pathogenesis of human B‐cell lymphoma and autoimmune disease. This review focuses upon a comparative analysis of CD40 versus LMP1 functions and mechanisms of action in B lymphocytes, discussing how this comparison can provide valuable information on both how CD40 signaling is normally regulated and how LMP1 disrupts the normal CD40 pathways, which can provide information of value to therapeutic design.