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Named after the two-faced Roman god of doorways, Janus kinases (JAKs) represent a class of tyrosine kinases. The JAK signaling pathway is pivotal for the downstream signaling of inflammatory cytokines, including interleukins, interferons, and multiple growth factors. This article provides an overview of the JAK pathway and signaling, its significance in immune-mediated dermatologic diseases and the development of a targeted, localized option of a selective JAK inhibitor, ruxolitinib cream. In the early 1990s, various discovery and clinical development programs were initiated to explore pharmaceutical inhibition of the JAK-STAT pathway. Incyte Corporation launched a strategy to identify molecules suitable for both topical as well as oral delivery. Ruxolitinib was designed as a molecule with low nanomolar potency selective for JAK1 and 2 enzymes, but without significant inhibition of non-JAK kinases, as well as physicochemical properties for both topical and oral administration. An oil-in-water emulsified ruxolitinib cream formulation was developed for topical application and was studied in multiple immune-mediated dermatologic diseases including psoriasis, alopecia areata, atopic dermatitis and vitiligo. Ruxolitinib cream represents a novel, JAK1/2 selective therapy that can be delivered directly to the skin to treat a number of cytokine-driven, inflammatory dermatoses. [ABSTRACT FROM AUTHOR]