During the 1980s CD46 was discovered in a search for C3b binding proteins of human peripheral blood cells. Its role as an inactivator of C3b and C4b deposited on self-tissue is highlighted by the observation that partial deficiency of CD46 is a predisposing factor to hemolytic uremic syndrome. This discovery has an impact on the treatment options for these patients. Other new findings have expanded the role of CD46 in immunity and disease. For example, signaling through CD46 on human T lymphocytes drives them to become regulatory cells, indicating a novel link between the complement system and cellular immunity. Also, CD46 interacts with at least seven human pathogens and participates in reproduction/fertilization, further suggesting that dissecting its multi-faceted activities will have important clinical implications.