Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agent in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent non-exclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors and several cell surface immunocompetent molecules. IVIg also has an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need of new strategies to overcome the predicted increasing worldwide shortage of IVIg.