The complement system is an essential component of the innate immune system that participates in elimination of pathogens and altered host cells and comprises an essential link between the innate and adaptive immune system. Soluble and membrane-bound complement regulators protect cells and tissues from unintended complement-mediated injury. Complement factor H is a soluble complement regulator essential for controlling the alternative pathway in blood and on cell surfaces. Normal recognition of self-cell markers (i.e. polyanions) and C3b/C3d fragments is necessary for factor H function. Inadequate recognition of host cell surfaces by factor H due to mutations and polymorphisms have been associated with complement-mediated tissue damage and disease. On the other hand, unwanted recognition of pathogens and altered self-cells (i.e. cancer) by factor H is used as an immune evasion strategy. This review will focus on the current knowledge related to these versatile recognition properties of factor H.