Itching is the predominant symptom of skin disease but it is ill-understood and a challenge for future research. Even the major nerve pathways for itch, and its relationship to pain are debatable. In inflamed skin, histamine plays a major role and its mode of release from mast cells in, for example, chronic urticaria is now better appreciated. Tachykinins including substance P and cytokines including interleukin-2 are evidently important peripherally. Opioid mu-receptor-dependent processes activate inhibitory circuits in the central nervous system and regulate the extent of intensity and quality of perceived itch. It is proposed that stimulation of large areas of skin such as by scratching, generates inhibitory activity which suppresses itch excitation. Therapeutic intervention based upon understanding these regulatory processes is a real prospect.