The thioredoxin fold is found in proteins that serve a wide variety of functions. Among these are peroxiredoxins, which catalyze the reduction of hydrogen peroxide and alkyl peroxides. Although the common structural fold shared by thioredoxins and peroxiredoxins suggests the possibility that they have evolved from a common progenitor, it has been difficult to examine this hypothesis in depth because pairwise sequence identities between proteins in these two superfamilies are statistically insignificant. Using the Shotgun program, we have found that sequences of reductases involved in maturation of cytochromes in certain bacteria bridge the sequences of thioredoxins and peroxiredoxins. Analysis of motifs found in a divergent set of thioredoxins, cytochrome maturation proteins, and peroxiredoxins provides further support for an evolutionary relationship between these proteins. Within the conserved motifs are specific residues that are characteristic of individual protein classes, and therefore are likely to be involved in the specific functions of those classes. We have used this information, in combination with existing structural and functional information, to gain new insight into the structure-function relationships in these proteins and to construct a model for the emergence of peroxiredoxins from a thioredoxin-like ancestor.