Complement is a major defense system of innate immunity and aimed to destroy microbes. One of the central complement regulators is factor H, which belongs to a protein family that includes CFHL1 and five factor H-related (CFHR) proteins. Recent evidence shows that factor H family proteins (factor H and CFHRs) are associated with diverse and severe human diseases and are also used by human pathogenic microbes for complement evasion. Therefore, dissecting the exact functions of the individual CFHR proteins will provide insights into the pathophysiology of such inflammatory and infectious diseases and will define the therapeutic potential of these proteins.