Insulin is a central player in the regulation of metabolic as well as non-metabolic cells: inefficient signal transduction (insulin resistance) not only represents the cornerstone in the pathogenesis of type 2 diabetes mellitus, but also drives atherosclerosis through inducing endothelial dysfunction. Last but not least epidermal homeostasis depends on insulin. We summarize the effects of insulin on proliferation and differentiation of human keratinocytes as well as the relevance of cytokine-induced insulin resistance for alterations in epidermal homeostasis characteristic for psoriasis. Kinases involved in both insulin- as well as cytokine-receptor signaling represent potential targets for innovative therapeutics. Such small molecules would primarily normalize "epidermal dysfunction", thus complementing the immunomodulatory strategies of today's biologics.