Open skin wounds are colonized with bacteria, and optimal wound care is required to prevent progression to infection. Intact skin normally provides protection from external environmental assaults. Disruption of the skin or tissue creating an open skin wound can result in infection, dehydration, hypothermia, scarring, compromised immunity, and changes in body image. Biofilms and bacterial genomics are areas of intense scientific investigation in the face of the emerging threat of bacterial resistance. Optimal wound care to prevent progression from colonization to infection remains the foundation of good clinical practice. On the basis of wound conditions, cleansing, debridement, measures to increase oxygenation and perfusion, adequate nutrition, and appropriate use of topical agents and antibiotics, when indicated, are the keys to managing open skin wounds. This article provides a targeted review of normal skin flora, wound healing, prevention of skin infection, colonization versus infection, biofilms, genomics and infectious disease, and management of open skin wounds.