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Summary: Background: Chronic pruritus is a distressing symptom associated with various dermatological conditions and systemic diseases. Current treatment options are often inadequate, resulting in impaired quality of life for many patients. An understanding of the underlying mechanisms of itch across pruritic conditions is important for development of effective, targeted treatments for chronic pruritus. Objectives: To provide an overview of the pathogenesis of chronic pruritus, focusing on the role of substance P (SP) and neurokinin 1 receptor (NK1R) in itch signalling, and to describe data supporting NK1R antagonism as a potential strategy for the treatment of chronic pruritus. Methods: A PubMed search was conducted to determine what data were available that investigated the role of SP and NK1R in itch signalling. Results: SP is a neuropeptide that is a mediator of itch signalling. One of the target receptors for SP is NK1R, which is expressed in the central nervous system and on multiple cell types involved in the initiation and transmission of itch. Studies demonstrating that SP and NK1R are overexpressed across multiple chronic itch‐inducing conditions and that NK1R antagonism disrupts itch signalling and reduces itch provide a rationale for targeting this pathway as a potential treatment of chronic pruritus across multiple diseases. Conclusions: A large and growing body of evidence, including recent phase II clinical studies of NK1R antagonists, demonstrate that SP and NK1R play an important role in itch signalling. Additional studies are ongoing to further evaluate the use of NK1R antagonists for the treatment of chronic pruritus. What's already known about this topic? Chronic pruritus has a significant impact on quality of life.Current treatment options for chronic pruritus are inadequate.Substance P (SP) and neurokinin 1 receptor (NK1R) have been shown to play a role in itch signalling, and may be a rational target for addressing chronic pruritus.NK1R antagonists are being evaluated as potential treatment for chronic pruritus. What does this study add? This review provides a compilation of the most up‐to‐date data elucidating the role of SP and NK1R in itch signalling, which supports targeting this pathway as a potential treatment of chronic pruritus.NK1R antagonism disrupts itch signalling and reduces itch.A summary of the latest data on NK1R antagonists in the treatment of pruritus is provided. Linked Editorial: Metz. Br J Dermatol 2019; 181:877–878. Plain language summary available online [ABSTRACT FROM AUTHOR]