Classification of itch into four categories-pruritoceptive, neurogenic, neuropathic, and psychogenic-has proven to be of utility to clinicians and investigators. Itch is recognized to be transmitted by dedicated afferent neurons, and a matrix of cerebral cortical loci involved in perception and the desire to scratch has been recognized. This highlights the multidimensional nature of the itch sensation. Some of the many mediators of itch, especially relevant in pruritogenic itch, are the result of cross-talk between dermal mast cells and adjacent cutaneous afferents. Keratinocytes of the epidermis express many neuropeptides, and their receptors are far from passive bystanders in the neurophysiology of itch. Mediators can also act centrally (eg, opioid peptides that act on micro receptors in the central nervous system). The pathophysiology of pruritus in neurogenic itch caused by common systemic diseases is gradually being elucidated, especially in the itch of cholestasis, although the molecular basis of itching in chronic renal failure remains elusive. Better understanding of the mediators of itch and their receptors has led to the imminent development of novel anti-itch compounds, including interleukin-31 inhibitors, histamine H4-receptor antagonists, and neurokinin-1 receptor antagonists.