Introduction: Urticaria, a mast cell-mediated skin disease, manifests as acute or chronic, with the latter divided into spontaneous and inducible types and requires individualized management, including identifying triggers and comorbidities. Antihistamines, particularly the second generation group, form the mainstay of primary treatment plans consisting of dosage adjustments and/or in combination with other treatment modalities depending on underlying disease control. Areas covered: A literature search was conducted using ‘antihistamines,’ ‘urticaria,’ ‘pharmacogenomics,’ ‘genomics,’ ‘biomarkers’ and ‘treatment response’ as key words. In this review, we focus on the comprehensive understanding and application of antihistamines in managing adult and adolescent patients with chronic urticaria. Expert opinion: Using antihistamines to treat urticaria is set to change significantly, focusing more on personalized medicine and identifying key biomarkers to enhance treatment response prediction. These changes aim to make treatments more specific and cost-effective by avoiding unnecessary tests. Applying new approaches in everyday clinical care faces challenges like proving the biomarkers’ reliability, updating current guidelines, and incorporating individualized treatments into standard procedures. Efforts should now concentrate on finding easy-to-use biomarkers, improving access to pharmacogenomics, understanding why some patients are resistant to treatment, and creating more specific treatment options based on patient needs.