This chapter presents the proteins of the alternative pathway and their special properties as enzymes, enzyme substrates, and regulators. The participation with the classical pathway components, C5–C9, in membrane attack is considered. The surprising discovery of the activation of the alternative pathway by many systems other than antibody is emphasized along with the key role played by C3 and its component parts. The alternative pathway of complement activation is closely linked to natural resistance to infections. The chapter discusses biological manifestations of alternative pathway activation. This area of research has been facilitated by isolated cytolytic alternative pathway that includes the five proteins of the membrane attack pathway. Thus, antibody-independent killing by the cytolytic pathway of bacterial and animal cells, including virus-infected human cells, is illuminated. The biomedical relevance of the alternative pathway as part of the complement system is unquestionable. Once activated, it can mark particles for phagocytosis, induce killing of nucleated cells or of bacteria, and cause lysis of enveloped viruses or virus-infected cells. It generates biologically active protein fragments, such as Bb, C3a, C3b, and C5a that influence function and behavior of inflammatory cells and cells of the immune system.