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The complement system is an important effector within the innate immune system as a defence against pathogens and maintaining homeostasis. Detection of pathogen- and damage-associated molecular patterns triggers the proteolytic cascade in complement. In healthy self-tissues effector proteins are tightly controlled by proteins acting as regulators of complement activation, and absence or malfunction of these regulators contribute to pathogenesis in a number of disease conditions in humans. Complement is highly relevant to nanomedicine due its role in adverse reactions on polymers and nanoparticle drug carriers, but also since complement hyperactivation contributes to pathogenesis in many disease conditions that are frequently addressed within nanomedicine. We review here the regulatory mechanisms that modulate complement activation and some of the most prominent cases linking complement dysregulation/deficiencies to pathogenesis as well as the strategies that have been considered for the development of therapeutic complement inhibitors and modulators to alleviate complement-mediated detrimental effects. In addition, this chapter summarizes the wealth of strategies adopted by pathogens to evade complement, such as inhibition of the proteolytic cascade, degradation of complement effector molecules and interference with transmembrane signaling by effectors, and highlights how structural and functional insight into their mode of function now provides leads for the development of novel complement therapeutics.