Prokineticin signaling comprises two secreted proteins (Prok-1 and Prok-2) and two cognate G-protein coupled receptors (PK-R1 and PK-R2) that are widely expressed in different tissues and of great versatility. Prokineticins were originally identified as the potent agents mediating gut motility in the digestive system, but were later shown to promote angiogenesis in steroidgenic glands, heart and reproductive organs. Prokineticins also modulate neurogenesis, circadian rhythms, nociception, haematopoiesis as well as immune response. Their diverse biological functions and functional complexity are exquisitely mediated by the distinct expression pattern and the multiple G-protein coupling of the receptors and ligands. Emerging evidence indicated that prokineticins are also associated with pathologies of the reproductive and nervous systems, myocardial infarction and tumorigenesis. The physiological and patho-physiological roles of prokineticin signaling are just beginning to be revealed and a better understanding of the system should lead to the development of useful therapies for various diseases.