Inflammation is a fundamental defense mechanism to protect the body from danger, which becomes potentially harmful if it turns chronic. Therapeutic strategies aimed at specifically blocking proinflammatory signals, particularly cytokines, such as IL-4, IL-6, IL-13, IL-17A, or TNF-α, have substantially improved our ability to effectively and safely treat chronic inflammatory diseases. Much less effort has been made to better understand the role of potential anti-inflammatory mechanisms. Here we summarize the current understanding of regulatory cell populations in the context of chronic inflammation, namely macrophages, Langerhans cells, myeloid-derived suppressor cells, and regulatory T and B lymphocytes. Emphasis is given to the skin because many different immune-related diseases occur in the skin. Development, phenotype, function, and evidence for their role in animal models of inflammation, as well as in the corresponding human diseases, are described. Finally, the feasibility of using regulatory cells as targets for potentially disease-modifying therapeutic strategies is discussed.