Intravenous immunoglobulins (IVIg) are concentrated formulations of human IgG prepared by industrial fractionation of large pools of individual plasma donations. IVIg were developed 20 years ago for the prophylaxis support of immunodeficient patients. However, IVIg have been increasingly used since 10 years, in the treatment of many autoimmune and inflammatory diseases raising the possibility of product shortages and ever increasing costs in the near future. Surprisingly, the immunomodulatory mechanisms of action of IVIg are unclear because of the diversity and often contradictory Fc, F(ab')(2), and non-IgG-related mechanisms that have been proposed from clinical observations and from results obtained in various in vitro and in vivo experimental models. These concepts are reviewed here and we discuss in more details three areas of active research, namely the mechanisms of IVIg action in Idiopathic Thrombocytopenic Purpura (ITP), the effects of IVIg on activated B lymphocytes and the possible involvement of autoantibodies of IgG isotype (auto-IgG) in the immunomodulatory effects of IVIg. The elucidation of the mechanisms of action of IVIg is crucial for a more rationalized clinical use of IVIg and for developing substitutes for some of the immunomodulatory indications in order to ensure long-term availability of plasma-derived IVIg for immunodeficient patients.