Pruritus (itch) can be defined as an unpleasant cutaneous sensation associated with the immediate desire to scratch. Recent findings have identified potential classes of endogenous “itch mediators” and establish a modern concept for the pathophysiology of pruritus. First, there in no universal peripheral itch mediator, but disease-specific sets of involved mediators. Second, numerous mediators of skin cells can activate and sensitize pruritic nerve endings, and even modulate their growth. Our knowledge of itch processing in the spinal cord and the involved centers in the central nervous system is rapidly growing. This review summarizes the current information about the significance of neuron–skin interactions, ion channels, neuropeptides, proteases, cannabinoids, opioids, kinins, cytokines, biogenic amines, neurotransmitters, and their receptors in the pathobiology of pruritus. A deeper understanding of these circuits is required for the development of novel antipruritic strategies.