The importance of immunoglobulin G (IgG) molecules for providing long-term sterile immunity as well as their major contribution to tissue inflammation during autoimmune diseases is generally accepted. In a similar manner, studies over the last years have elucidated many details of the molecular and cellular pathways underlying this protective activity in vivo, emphasizing the role of cellular recognizing the constant antibody fragment. In contrast, the active anti-inflammatory activity of IgG, despite being known and actually identified in human autoimmune patients more than 30 years ago, is much less defined. Recent evidence from several independent model systems suggests that IgG glycosylation is critical for the immunomodulatory activity of IgG and that both monomeric IgG as well as IgG immune complexes can diminish Fc receptor and complement dependent inflammatory processes. Moreover, there is increasing evidence that IgG molecules also modulate B and T cell responses, which may suggest that IgG is centrally involved in the establishment and maintenance of immune homeostasis.