The skin forms an essential barrier between the inside of an organism and the environment. In addition to its function in insulation, temperature regulation, and sensation, it protects the body against physical trauma, pathogens, UV radiation, and excessive water loss. Many processes necessary for maintaining the skin integrity, including antimicrobial/antiviral defense, wound healing, and removal of tumors, are regulated by cytokines. Accumulating results lead us to assume that interleukin (IL)-28 and IL-29, 2 novel members of the IL-10-interferon cytokine family, are important regulators of some of these processes. In the skin, IL-28 and IL-29 can be produced by virus-infected cells, maturing dendritic cells (DCs), and regulatory T-cells, and they mainly influence keratinocytes and melanocytes. In keratinocytes, IL-28 and IL-29 induce growth inhibition. Simultaneously, these cytokines increase the cellular synthesis of proteins that directly hinder virus replication and enhance the readiness to present viral antigens to immune cells. Further, IL-28 and IL-29 upregulate expression of viral and microbial sensing cellular receptors, including toll-like receptor (TLR)3, TLR2, and melanoma differentiation associated gene 5, and strengthen the cellular response to these receptors' ligands. Thereby, in the noninfected skin IL-28 and IL-29 enhance the capacity of keratinocytes to react to viral and microbial products and at least indirectly upregulate their inflammatory potential and innate immunity. IL-28 and IL-29 can act synergistically with other mediators secreted during DC maturation (eg, IL-20). In summary, IL-28/IL-29 may play an important role in the skin in the clearance of viral and microbial infections and in the removal of tumors.