Itch is an unpleasant sensation arising from a variety of dermatologic, neuropathic, systemic, and psychogenic etiologies. Various itch pathways are implicated according to the underlying etiology. A variety of pruritogens, or itch mediators, as well as receptors have been identified and provide potential therapeutic targets. Recent research has primarily focused on targeting inflammatory cytokines and Janus kinase signaling, protease-activated receptors, substance P and neurokinin, transient receptor potential-vanilloid ion channels, Mas-related G-protein-coupled receptors (MRGPRX2 and MRGPRX4), the endogenous opioid and cannabinoid balance, and phosphodiesterase 4. Periostin, a newly identified pruritogen, should be further explored with clinical trials. Drugs targeting neural sensitization including the gabergic system and P2X3 are other potential drugs for chronic itch. There is a need for more targeted therapies to improve clinical outcomes and reduce side effects.