Inhibitor of nuclear factor κB kinase-α (IKKα) is required for maintaining skin homeostasis and preventing skin tumorigenesis. However, its signaling has not been extensively investigated. In the present study, we generated two mouse lines that expressed different levels of transgenic IKKα in the basal epidermis under the control of keratin-5 promoter and further evaluated their effects on the major pathways of inflammation, proliferation, and differentiation in the skin. Regardless of the transgenic IKKα levels, the mice develop normally. Because IKKα deletion in keratinocytes blocks terminal differentiation and induces epidermal hyperplasia and skin inflammation, we depleted the endogenous IKKα in these transgenic mice and found that the transgenic IKKα represses epidermal thickness and induces terminal differentiation in a dose-dependent manner. Also, transgenic IKKα was found to elevate expression of Max dimer protein 1 (Mad1) and ovo-like 1, c-Myc antagonists, but repress activities of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Jun-amino-terminal kinases, c-Jun, signal transducer and activator of transcription 3 (Stat3), and growth factor levels in a dose-dependent fashion in the skin. Moreover, EGFR reduction represses IKKα deletion-induced excessive ERK, Stat3 and c-Jun activities, and skin inflammation. These new findings indicate that elevated IKKα expression not only represses epidermal thickness and induces terminal differentiation, but also suppresses skin inflammation by an integrated loop. Thus, IKKα maintains skin homeostasis through a broad range of signaling pathways.