Abstract Cobra venom factor (CVF) is the complement-activating protein in cobra venom. This manuscript reviews the structure and function of CVF, how it interacts with the complement system, the structural and functional homology to complement component C3, and the use of CVF as an experimental tool to decomplement laboratory animals to study the functions of complement in host defense and immune response as well as in the pathogenesis of diseases. This manuscript also reviews the recent progress in using the homology between CVF and C3 to study C3 structure and function, and to develop human C3 derivatives with the complement-depleting function of CVF. These human C3 derivatives represent humanized CVF, and are a conceptually different concept for pharmacological intervention of the complement system, therapeutic complement depletion. The use of humanized CVF for therapeutic complement depletion in several pre-clinical models of human diseases is also reviewed.