The immune system protects the host from pathogenic microbes, but tight regulation of the evoked response is requisite to limit bystander damage. The interleukin (IL)-10 family of cytokines, composed of 9 members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and 3 distantly related members, IL-28A, IL-28B, and IL-29, plays a central role in this regulation. IL-10 family cytokines emerged before the adaptive immune response and elicit diverse host defense mechanisms, especially from epithelial cells during an infection. IL-10 family cytokines are also essential for maintenance and integrity of tissue epithelial layers. These cytokines promote innate immune responses from tissue epithelia that limit the damage caused by both viral and bacterial infections. They also facilitate tissue healing after infection/inflammation. In this regard, IL-10 suppresses pro-inflammatory responses, limiting tissue disruption resulting from an inflammatory response. Thus, a central functional theme of IL-10 family cytokines is their role in tissue protection. This review focuses on IL-10, the founding member of this family of cytokines, and integrates recent data on the function and regulation of IL-10 during bacterial infections. Emphasis is placed on the role of IL-10 in Pseudomonas aeruginosa keratitis and the subsequent infectious/inflammatory processes evoked.