Endogenously produced nitric oxide (NO) has a remarkably diverse range of biological functions, including a role in neurotransmission, smooth muscle relaxation, and the response to immunogens. Over the last 10 years, it has become clear that this extraordinary molecular messenger also plays a vital role in the skin, orchestrating normal regulatory processes and underlying some of the pathophysiological ones. We thought it pertinent to review the current literature concerning the possible function of NO in normal skin, its clinical and pathological significance, and the potential for therapeutic advances. The keratinocytes, which make up the bulk of the epidermis, constitutively express the neuronal isoform of NO synthase (NOS1), whereas the fibroblasts in the dermis and other cell types in the skin express the endothelial isoform (NOS3). Under certain conditions, virtually all skin cells appear to be capable of expressing the inducible NOS isoform (NOS2). The expression of NOS2 is also strongly implicated in psoriasis and other inflammatory skin conditions. Constitutive, low level NO production in the skin seems to play a role in the maintenance of barrier function and in determining blood flow rate in the microvasculature. Higher levels of NOS activity, stimulated by ultraviolet (UV) light or skin wounding, initiate other more complex reactions that require the orchestration of various cell types in a variety of spatially and temporally coordinated sets of responses. The NO liberated following UV irradiation plays a significant role in initiating melanogenesis, erythema, and immunosuppression. New evidence suggests that it may also be involved in protecting the keratinocytes against UV-induced apoptosis. The enhanced NOS activity in skin wounding (reviewed recently in this journal [Nitric oxide 7 (2002) 1]) appears to be important in guiding the infiltrating white blood cells and initiating the inflammation. In response to both insults, UV irradiation and skin wounding, the activation of constitutive NOS proceeds and overlaps with the expression of NOS2. Thus, at a macro-level, at least three different rates of NO production can occur in the skin, which seem to play an important part in organizing the skin's unique adaptability and function.