Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angio-oedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab and ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton's tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This Therapeutics article focuses on the evidence for these novel drugs and their role in addressing an unmet need for personalised management of patients with chronic urticaria., Competing Interests: Declaration of interests TZ has received honoraria for lectures from Amgen, AstraZeneca, AbbVie, ALK–Abelló, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES Farma, HAL Allergy, Henkel, Kryolan, Leti, L'Oreal, Meda, Menarini, Merck Sharp & Dohme, Novartis, Nuocor, Pfizer, Sanofi, Stallergenes, Takeda, Teva, Union Chimique Belge, and Uriach; fees for industry consulting from Abivax, Almirall, Bluprint, Celldex, Celltrion, Novartis, and Sanofi; he declares unpaid organisational affiliations: is a committee member of Allergic Rhinitis and its Impact on Asthma, is a member of the board of the German Society for Allergy and Clinical Immunology (DGAKI), head of the European Centre for Allergy Research Foundation (ECARF), President of the Global Allergy and Asthma European Network (GA(2)LEN), member of the committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). LFE reports honoraria for lectures from Novartis, Sanofi, and Abbvie; and participation on an advisory board for Sanofi. AG-A reports grants from Uriach Pharma, Novartis, Instituto Carlos III-FEDER (PI11/00108); consulting fees from Uriach Pharma, Neucor, Genentech, Novartis, FAES Farma, GlaxoSmithKline, Sanofi–Regeneron, Amgen, Thermo Fisher Scientific, Almirall, Leo Pharma, Mitsubishi Tanabe, and Servier; honoraria for lectures and education from Uriach Pharma, Novartis, Genentech, Menarini, LEO-PHARMA, GlaxoSmithKline, Merck Sharp & Dohme, Almirall, Sanofi, and Avene; and participates on an advisory board for Celldex Therapeutics. CG has a consultancy with Celltrion and is on steering committees for AB Science and Blueprint Medicines. EK reports honoraria for lectures and consulting from Novartis. KK reports grants from Novartis (NCT05032157, NCT05513001, NCT06042478); and personal fees from Novartis, Menarini, and Takeda, outside the submitted work. PK reports personal fees from Novartis, Roche, and ValenzaBio, outside the submitted work. MM is or recently was a speaker, advisor, or both, for Allakos, Alexion, Almirall, Alvotech, Amgen, Aquestive, Arcensus, argenX, AstraZeneca, Astria, BioCryst, Blueprint, Celldex, Celltrion, Clinuvel, Cogent, CSL Behring, Escient, Evoemmune, Excellergy, GlaxoSmithKline, Incyte, Jasper, Kashiv, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie, Noucor, Novartis, Orion Biotechnoloy, Pharvaris, Resonance Medicine, Sanofi–Regeneron, Santa Ana Bio, Septerna, Servier, Takeda, Teva, Third HarmonicBio, Valenza Bio, Vitalli Bio, Yuhan Corporation, and Zurabio; and he received institutional research funding from Allakos, Alexion, Amgen, AstraZeneca, Astria, BioCryst, Blueprint, Celldex, Clinuvel, Cogent, CSL Behring, Escient, Evommune, Incyte, Jasper, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Mitsubishi Tanabe Pharma, Noucor, Novartis, Pharvaris, Sanofi–Regeneron, Santa Ana Bio, Septerna, Servier, Takeda, ThirdHarmonicBio, and Yuhan Corporation., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)