Chronic urticaria (CU) is a long-lasting and distressing condition that impairs patient quality of life (QoL) by disrupting sleep and diminishing work/school productivity. Thus treatment should not only be safe and effective but also not add to this impairment or increase risks to health or safety. Non-sedating second-generation antihistamines, with their long duration of action, pharmacodynamic properties that allow once-daily dosing and lack of drug–drug interactions and sedative effects, are the first-line symptomatic treatment option, but some patients have no adequate response to standard doses of these medications. Other therapeutic approaches to refractory urticaria have been suggested but have been limited by sparse clinical data and/or significant adverse effect profiles. Although discouraged by treatment guidelines, sedating antihistamines are frequently prescribed for nighttime use when urticaria symptoms are severe as add-on therapy to a non-sedating antihistamine. However, their pronounced effects on rapid eye movement sleep and hangover negatively impact QoL, learning and performance, and limit their use for patients in occupations that require alertness. For patients who do not respond adequately to standard doses of non-sedating second-generation antihistamines, increasing the dose of non-sedating antihistamines thus may represent the safest therapeutic approach. Given the fact that only few controlled studies have assessed the efficacy and safety of high-dose non-sedating antihistamines in CU, patient safety should be a key consideration when choosing a specific antihistamine.