In hair growth, as the follicle bulb cells rapidly differentiate into either cortical or cuticle hair keratinocytes, about 50-100 keratin genes are transcriptionally activated. However, this complexity can be reduced to several, highly conserved gene families. In studying the regulation of keratin gene expression in the hair follicle we have isolated genes from most of these families and have examined their expression patterns by in situ hybridization. In the cortical keratinocytes striking patterns of keratin gene expression exist, suggesting that different transcriptional hierarchies operate in the various cell types. Comparisons of the keratin gene promoter regions indicates conserved sequence motifs that could be involved in determining these cell specificities. Similarly, we have isolated related sheep and human cuticle keratin genes and find conserved DNA motifs and expression patterns in cuticle cell differentiation. Additionally, the expression of sheep wool follicle IF and high-sulfur keratin genes in transgenic mice suggests that the regulatory DNA elements and proteins of hair keratin genes are functionally conserved between mammals.