C1 is a multimolecular complex that initiates the classical pathway of complement. It is composed of the pattern recognition component C1q and the serine proteases C1r and C1s. Activation of C1 elicits a series of potent effector mechanisms directed at limiting infection by invading pathogens as well as participating in other biological functions such as immune tolerance. While many molecules in addition to antibody have been demonstrated to activate C1, only a handful of C1 inhibitors have been described. Disregulated control of complement activation is associated with numerous autoimmune and inflammatory disease processes, thus tight regulation of C1 activation is highly desirable. We have recently discovered a novel inhibitor of C1, the coat protein of the human astroviruses, a family of enteric pathogens that infect young children. The astrovirus coat protein binds to the A-chain of C1q and inhibits spontaneous as well as antibody-mediated activation of the C1 complex resulting in suppression of classical pathway activation and complement-mediated terminal effector functions. This is the first description of a non-enveloped icosahedral virus inhibiting complement activation and the first description of a viral inhibitor of C1. The known inhibitors of C1 are reviewed and then discussed in the context of this novel viral C1 inhibitor. Additionally, the properties of this compound are elucidated highlighting its potential as an anti-complement therapeutic for the many diseases associated with inappropriate complement activation.