Pruritus is the most common symptom secondary to skin diseases. Advances in the fields of neurobiology, immunology and physiology have made it possible for us to understand and unravel the deeper pathophysiological basis of pruritus. This review aims to update our current understanding of the mechanisms and mediators of pruritus. Special attention is paid to endogenous itch mediators particularly newly identified ones like endovanilloids, opioids, neurotrophins, cannabinoids, proteases and cytokines. Various theories explaining the peripheral encoding of itch are reviewed. Multiple neural pathways including the central itch pathways as well as supraspinal processing of itch and brain areas involved in pruritus are highlighted. Apart from peripheral itch mediators, spinal neural receptors are also involved in control of itch and should form part of the development of a novel antipruritic strategy. Further studies are required to fill the lacunae in our current understanding of the pathophysiology of pruritus.