The alternative complement pathway is a self-contained and independent recognition and effector pathway that evolved to protect the host from microbes. As such, it must separate self from non-self. Via low grade continuous turnover (tickover) of the pivotal C3 component, the alternative complement pathway is always on guard to defend the host. Activated C3 binds continuously to self tissue and to foreign tissue, if present. There is no apparent discrimination at this initiation step. However, the amplification of C3 deposition on self (but not foreign) tissue, a necessity in establishing the effector functions of this pathway, is inhibited by a series of functionally, structurally and genetically related plasma and membrane glycoproteins which down-regulate complement activation. These regulatory molecules are widely distributed on human tissue. The plasma proteins are preferentially active on fluid-phase components while membrane-bound forms act on cell-bound components. Here, John Atkinson and Timothy Farries discuss these inhibitors of complement activation and suggest that their action explains the ability of the alternative pathway to amplify on foreign tissue but be down-regulated on autologous tissue.