Recent studies revealed that animal toxins with unrelated biological functions often possess a similar architecture. To tentatively understand the evolutionary mechanisms that may govern this principle of functional prodigality associated with a structural economy, two complementary approaches were considered. One of them consisted of investigating the rates of mutations that occur in cDNAs and/or genes that encode a variety of toxins with the same fold. This approach was largely adopted with phospholipases A2 from Viperidae and to a lesser extent with three-fingered toxins from Elapidae and Hydrophiidae. Another approach consisted of investigating how a given fold can accommodate distinct functional topographies. Thus, a number of topologies by which three-fingered toxins exert distinct functions were investigated either by making chemical modifications and/or mutational analyses or by studying the three-dimensional structure of toxin-target complexes. This review shows that, although the two approaches are different, they commonly indicate that most if not all the surface of a snake toxin fold undergoes natural engineering, which may be associated with an accelerated rate of evolution. The biochemical process by which this phenomenon occurs remains unknown.