Sepsis represents a perplexing challenge for the innate immune system. In response to microbial challenge, an immunocompetent host initiates an immediate robust response to contain and clear infection. However, if the infection is not controlled and spreads beyond the local site, this pervasive immune response, once systemic, often results in detrimental complications such as systemic inflammatory response syndrome, multiple organ failure, and immune paralysis, contributing to the high mortality observed in sepsis. Resident tissue macrophages, as sentinels of the host immune response to infection, are responsible for recognition of infection through several pattern recognition molecules and initiation of a complex cytokine/chemokine cascade. Chemokines are central mediators involved in recruitment of specific leukocyte populations to the site of infection, differentiation of classically- and alternatively-activated macrophages, and regulation of important processes such as pathogen phagocytosis and killing, release of reactive oxygen intermediates and proteases, and subsequent chemokine production. This review explores the role of the peritoneal macrophage and the importance of chemokines in macrophage activation during septic peritonitis. Continued investigation of chemokines and their mechanisms of action will provide valuable insight into the development of effective clinical therapeutics for the treatment of sepsis as well as other inflammatory disorders.