Complement 3 (C3) is a crucial component of the innate immune system, which in association with other complement proteins, forms a major host mechanism for detection and clearance of potential pathogens. The central role of the complement system and its polymorphism has already been studied extensively. Although the identification of C3 in echinoderms and tunicates suggests that this multifunctional protein emerged at least 700 million years ago, the underlying functional difference between C3S and C3F variants have not yet been clearly demonstrated. Focussing on the examined associations between C3F and C3S polymorphisms and disease states, the presence of the C3F allele has generally been linked with a detrimental outcome. In this review the general characteristics and analytical aspects of C3 and the knowledge about the biological and clinical consequences of C3 polymorphism have been summarised.