Membrane Attack Complex/Perforin (MACPF) and Cholesterol-Dependent Cytolysins (CDC) form the MACPF/CDC superfamily of important effector proteins widespread in nature. MACPFs and CDCs were discovered separately with no sequence similarity at that stage being apparent between the two protein families such that they were not, until recently, considered evolutionary related. The breakthrough showing they are came with recent structural work that also shed light on the molecular mechanism of action of various MACPF proteins. Similarity in structural properties and conserved functional features indicate that both protein families have the same evolutionary origin. We will describe the distribution of MACPF/CDC proteins in nature and discuss briefly their similarity and functional role in different biological processes.