Keratinocytes undergo a distinct pattern of proliferation and differentiation that is essential for the function of the skin as a protective barrier. Defects in the equilibrium between proliferation and differentiation compromise the skin's barrier function and give rise to human diseases such as psoriasis and nonmelanoma skin cancer. The identification of protein kinase C (PKC) as a major cellular target for tumor-promoting phorbol esters suggested the involvement of this enzyme in the regulation of keratinocyte proliferation and tumorigenesis; however, results have demonstrated the existence in keratinocytes and other cell types of another diacylglycerol/phorbol ester-responsive protein kinase: protein kinase D (PKD) in mouse, also known as PKC micro in humans. Although numerous data suggest the importance of PKD/PKC micro in processes related to proliferation in many cell types, including keratinocytes, there are no specific inhibitors of PKD currently available. Current treatment strategies for hyperproliferative skin disorders are often suboptimal, either because of lack of efficacy or because of contraindications due to deleterious side effects or aesthetic considerations. Thus, PKD/PKC micro may represent a novel target for the development of new and more efficacious drug treatments for hyperproliferative skin disorders.