MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease. It now becomes evident that in addition to C3NeF, which inhibits the inactivation of the alternative C3 convertase C3bBb, different genetically determined factors are also involved in the pathogenesis of MPGN II. These factors though different from C3NeF also result in defective complement regulation acting either through separate pathways or synergistically with C3NeF. Following the finding of MPGN II in Factor H deficient animals, patients with MPGN II were identified presenting with an activated complement system caused by Factor H deficiency. Factor H gene mutations result in a lack of plasma Factor H or in a functional defect of Factor H protein. Loss of Factor H function can also be caused by inactivating Factor H autoantibodies, C3 mutations preventing interaction between C3 and Factor H, or autoantibodies against C3. Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress.