The complement system is a powerful part of the host innate immune defense and is aimed to damage and eliminate microbes and modified self-cells. To protect host cells and biological surfaces from damage mediated by complement activation products a tight control of the complement system is necessary. Imbalances in complement regulation contribute to tissue injury and can result in autoimmune diseases such as hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (MPGN) or age related macular degeneration (AMD). Disease associated mutations have been identified in several complement regulators or components, such as members of the factor H protein family. This group includes the major alternative pathway regulator, complement factor H (CFH) and five complement factor H related proteins (CFHR). Homozygous chromosomal deletion of a genomic 84kb, chromosomal fragment which includes the genes CFHR1/CFHR3 is a risk factor for hemolytic uremic syndrome (HUS) at young age and is predominantly associated with the generation of autoantibodies to CFH, leading to a specific type of HUS, called DEAP (deficiency of CFHR and autoantibody positive)—HUS. The same deletion however is protective to the development of age related macular degeneration (AMD) in elderly people. Thus CFHR1 and CFHR3 proteins, and likely also the other members of this gene family are linked to human diseases. We here summarize the current knowledge about the role or association of CFHR1 and CFHR3 in the human diseases HUS and AMD.