Nanoparticles are being increasingly implemented in drug delivery and diagnostic systems, as they show promising features in protected, targeted and sustained delivery of active pharmaceutical ingredients and contrast agents. Following intravenous injection, nanoparticles, depending on their physicochemical properties, may trigger the complement system, which is a major part of the innate immune system. Complement activation and fixation can prime the surface of nanoparticles for rapid recognition and clearance by complement receptor bearing cells such as blood monocytes and macrophages of the reticuloendothelial system. Uncontrolled complement activation can also induce adverse reactions, and these have been reported with regulatory approved nanomedicines, including stealth therapeutics. We discuss on the interaction between the complement system and synthetic surfaces, and comment on general physicochemical parameters that incite complement. State-of-the-art approaches for evaluation and determination of complement activation and sensing are also described.