During both short- and long-duration spaceflight, several health problems can occur, including those of the skin. Astronauts in space and after returning to earth experience erythematous, burning, itchy, dry, sensitive, and thinning skin. Other skin problems, such as infections, abrasions, lacerations, delayed wound healing, and accelerated skin aging, are also common. Human skin is an ecosystem composed of a wide range of habitats for bacteria, fungi, and viruses called microbiome, which not only show a strong skin site-specific preference but also serve as microbial fingerprints that are highly unique to individuals. These human skin-associated microorganisms make a substantial contribution to the microbial ecosystems that inhabit the closed environments in space. On the other hand, human skin microbiome is also subject to change during spaceflight, which may lead to skin infections or the flare up of skin diseases. This review highlights some of the interactions between the space environment and the skin.