IgA nephropathy (Berger disease) is defined by the dominant or codominant deposition of IgA in the renal mesangium. There is much evidence in vitro to suggest up-regulation of the IgA immune response in patients. Data from tonsillar and bone marrow-derived lymphocytes and from in vivo immunization studies indicate that the primary defect is an up-regulated systemic one, rather than mucosal IgA production. Several lines of evidence suggest that increased IgA production alone is inadequate to explain the pathogenesis of Berger disease. Murine models of IgA nephropathy indicate that local complement activation mediated by deposited IgG is essential for mesangial cell proliferation and subsequent renal injury. Circulating immune complexes from patients with Berger disease contain IgA and IgG within the same lattice. In vitro studies of model immune aggregates containing various mixtures of IgA and IgG indicate that the IgG is the site of complement activation and fixation. The IgA in the aggregate actually inhibits both complement activation and binding to erythrocyte complement receptor CR1. This effect of IgA may prevent effective immune complex clearance. In future studies, more emphasis should be placed on the roles of IgG and complement in the pathogenesis of IgA nephropathy.