Peripheral injury precipitates the release and accumulation of extracellular molecules at the site of injury. Although these molecules exist in various forms, they activate specific receptor classes expressed on primary afferent neurons to mediate cellular and behavioral responses to both nonpainful and painful stimuli. These inflammatory mediators and subsequent receptor-mediated effects exist to warn an organism of future injury, thereby resulting in protection and rehabilitation of the wounded tissue. In this chapter, inflammatory mediators, their target receptor classes, and downstream signaling pathways are identified and discussed within the context of inflammatory hyperalgesia. Furthermore, scaffolding mechanisms that exist to support inflammatory signaling in peripheral afferent neuronal tissues specifically are identified and discussed. Together, the mediators, pathways, and scaffolding mechanisms involved in inflammatory hyperalgesia provide a unique knowledge point from which new therapeutic targets can be understood.