Intravenous immunoglobulin (IVIG) is the mainstay of therapy for humoral immune deficiencies and numerous inflammatory disorders. Although the use of IVIG may be supplanted by several targeted therapies to cytokines, the ability of polyclonal normal IgG to act as an effector molecule as well as a regulatory molecule is a clear example of the polyfunctionality of IVIG. This article will address the mechanism of action of IVIG in a number of important conditions that are otherwise resistant to treatment. In this commentary, we will highlight mechanistic studies that shed light on the action of IVIG. This will be approached by identifying effects that are both common and disease-specific, targeting actions that have been demonstrated on cells and processes that represent both innate and adaptive immune responses.