Mutations in the genes for three complement regulators-complement factor H (CFH), membrane cofactor protein (MCP), and factor I (IF)-have now been described in patients with atypical HUS. The functional effects of these mutations have been studied in detail and have been shown to affect secretion, expression, and regulatory function. Genotype-phenotype correlations have shown that the majority of patients with CFH, MCP, and FI mutations develop end-stage renal failure. The outcome of transplantation is poor in patients known to have either a CFH or FI mutation, with approximately 80% of patients losing the graft to recurrent disease within 2 years. In contrast, patients known to have only an MCP mutation have a satisfactory transplantation outcome. This is expected because MCP is a transmembrane regulator and allografts will therefore be protected by wild-type MCP. Combined liver/kidney transplantation for patients known to have a CFH mutation has not been successful to date. There is optimism that in the future, targeted complement inhibitors will be of major therapeutic benefit in this condition.