Prokineticins (PK) 1 and 2 belong to a new family of chemokines capable to interact with two different G coupled receptors: Prokineticin receptor (PKR)1 and 2. Both prokineticins and their receptors are widely distributed in different tissues and regulate several biological functions. In particular, a role of the PK system in inflammation and nociception has been established. PKRs are expressed in regions of the nervous system associated with pain and in primary sensitive neurons they colocalize with transient potential receptor vanilloid–TRPV1 providing an anatomical interaction in nociceptor sensitization. Moreover, PKs are strongly upregulated in immune and glial cells and sustain a proinflammatory loop in inflamed tissues. Recent evidences indicate that the block of the PK system represents a promising strategy to contrast inflammation and pain.