A number of proteins anchored on the cell surface function to protect host tissues from bystander injury when complement is activated. In humans, they include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and CD59. Although disease conditions directly attributable to abnormal function of these proteins are relatively rare, it has become evident from recent studies using animal models that membrane complement regulatory proteins are important modulators of tissue injury in many autoimmune and inflammatory disease settings. Evidence is also emerging to support a role of these proteins in regulating cellular immunity. In this article, we highlight recent advances on the in vivo biology of membrane complement regulatory proteins and discuss their relevance in human disease pathogenesis and therapeutics.