Chronic pruritus remains a central societal issue because of its high occurrence and the substantial decrease in quality of life it may cause to affected individuals. Not only dermatological conditions, but also systemic, neurological, or psychiatric diseases may lead to chronic pruritus. Additionally, various underlying conditions may coexist or the cause may be unknown. Due to its heterogeneity, the therapeutic approach is complex and remains a challenge for the clinician. Basic measures such as emollients to avoid xerosis and treatment of the underlying disease should be initiated regardless of the duration of the symptom. Depending on the indication, other topical (e.g., calcineurin inhibitors, topical corticosteroids, capsaicin) and systemic agents (immunosuppressive drugs, gabapentinoids, antidepressants, mu-opioid receptor antagonists) may provide further relief. Additionally, accompanying disorders such as sleep impairment, depression, or anxiety should also be treated. New insights into pathways involved in the development and maintenance of chronic pruritus have led in the past years to the development of a considerable number of novel antipruritic drugs. Several randomized controlled trials have been recently completed or are currently underway testing biological compounds with promising approaches. These include antagonists for nerve growth factor, neuropeptides, histamine 4 receptors, certain interleukin receptors, and opioid receptors.