Intravenous immunoglobulin (IVIG) products are derived from pooled human plasma and have been used for the treatment of primary immunodeficiency disorders for more than 25 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders; however, the precise mechanism(s) of action is not known. Recent investigations suggest that IVIG has a much broader ability to regulate cellular immunity including innate and adaptive components. IVIG is also a recently recognized modifier of complement activation and injury. Here, we discuss these important advancements and how this knowledge applies to desensitization protocols and to the treatment of antibody-mediated rejection.