SPRR genes encode a novel class of polypeptides called small proline-rich proteins that are strongly induced during differentiation of human epidermal keratinocytes in vitro and in vivo.The most characteristic feature of the SPRR gene family resides in the structure of the central segment of the encoded polypeptides that have built up from tandemly repeated units of either 8 (in SPRR1 and SPRR3) or 9 (in SPRR2) amino acids with the general consensus *K*PEP**. The sequence of the different members of this family of genes together with their clustered chromosomal organization strongly suggests that these genes have evolved from a single progenitor gene by multiple intra- and intergenic duplications. Analysis of the different SPRR subfamilies revealed a gene-specific bias to either intra- and intergenic duplication.