Nitric oxide (NO) plays an important role in the maintenance and regulation of the skin and the integrity of its environment. Derangement of NO production is implicated in the etiology of a multitude of dermatologic diseases, indicating future therapeutic directions. In an era of increasing resistance rates to available antibiotics and subpar development of new agents, NO is promising as a prospective topical broad-spectrum antimicrobial agent with small likelihood of resistance development. Because the greatest strides have been made in the setting of infectious disease and skin and soft-tissue infection, this will be a major focus of this article. In addition, we will review NO's role in skin regulation and dysregulation, immune function, the various topical release systems that have been devised and tested, NO's relation to UV radiation and skin pigmentation, and finally, its potential applications as a cosmeceutical.