Urea is an important hygroscopic component of the epidermis, where it participates in the maintenance of skin hydration as part of the skin's source of natural moisturizing factor (NMF) in the outer most layers. Xerotic skin, which is frequently characterized as NMF-deficient, is a unifying trait of dermatoses such as atopic dermatitis (AD), psoriasis, and ichthyosis vulgaris. The reduced hygroscopic potential of pathologically dry skin leads to unregulated transepidermal water loss (TEWL), epidermal hyperproliferation, and inhibited desquamation; all which clinically translate to hyperkeratotic and possibly pruritic skin. Common underlying etiologies link these dermatoses to aberrant expression of genes encoding epidermal structural and catalytic proteins. Intervention of dry skin pathologies with topical moisturizer formulations is a foundational management strategy. For over a century urea-containing formulations have been used in a concentration-dependent manner to restore skin hydration, thin hyperkeratosis, debride dystrophic nails, and enhance topical drug penetration. Recently, urea's role in skin hydration and repair has expanded to include regulation of epidermal genes necessary for proper barrier function. Taken together, urea's versatility in topical formulations and broad range of therapeutic mechanism highlights its utility to clinicians and benefit to patients.<br /><br /> <em>J Drugs Dermatol</em>. 2016;15(5):633-639.