Pruritus is the most common symptom of dermatologic and systemic diseases. The diagnosis of pruritus is clinical, although additional tests may be necessary to identify or confirm the cause. Translational medicine has led to the discovery of new mediators of itch, or pruritogens, as well as new receptors. Knowing how to properly recognize the main pathway that mediates itch in each patient is the key to successful treatment. Although the histaminergic pathway predominates in conditions like urticaria or drug-induced pruritus, it is the nonhistaminergic pathway that predominates in nearly all other skin diseases covered in this review. Part 1 of this 2-part review discusses the classification of pruritus, additional testing, the pathophysiology of itch and the pruritogens implicated (including cytokines and other molecules), and central sensitization to itch.