Tissue injury, whether by trauma, surgical intervention, metabolic dysfunction, ischemia, or infection, evokes a complex cellular response (inflammation) that is associated with painful hyperalgesic states. Although in the acute stages it is necessary for protective reflexes and wound healing, inflammation may persist well beyond the need for tissue repair or survival. Prolonged inflammation may well represent the greatest challenge mammalian organisms face, as it can lead to chronic painful conditions, organ dysfunction, morbidity, and death. The complexity of the inflammatory response reflects not only the inciting event (infection, trauma, surgery, cancer, or autoimmune) but also the involvement of heterogeneous cell types including neuronal (primary afferents, sensory ganglion, and spinal cord), non-neuronal (endothelial, keratinocytes, epithelial, and fibroblasts), and immune cells. In this commentary, we will examine 1.) the expression and regulation of two members of the transient receptor potential family in primary afferent nociceptors and their activation/regulation by products of inflammation, 2.) the role of innate immune pathways that drive inflammation, and 3.) the central nervous system's response to injury with a focus on the activation of spinal microglia driving painful hyperalgesic states.