Growing evidence implicates an increasing number of novel lipids, including eicosanoids, diacylglycerols, lysophosphatidic acids and ceramides, in augmenting the sensitivity of sensory neurons and enhancing pain perception. Many of these lipids are second messengers in signaling pathways that are associated with increasing the sensitivity of sensory neurons, whereas others are putative inflammatory mediators that activate either surface receptors or ion channels in these neurons. Based on the studies we review, it is clear that lipid-derived inflammatory mediators are a novel group of targets for therapeutics to treat inflammation and chronic pain states. However, much work remains to define the roles of these lipids in inflammation and the cellular mechanisms by which they alter the sensitivity of sensory neurons.