The recent growth in structural data, and ensuing analyses, have revealed the structural and functional versatility of protein families. With respect to enzymes, local active-site mutations, variations in surface loops and recruitment of additional domains accommodate the diverse substrate specificities and catalytic activities observed within several superfamilies. Conversely, some functions have more than one structural solution, having evolved independently several times during evolution. Combined with the existence of multi-functional genes, which have arisen by gene recruitment, these phenomena must be considered in the process of genome annotation.