Oral second-generation antihistamines (sgAH) constitute the first-line treatment for chronic spontaneous urticaria (CSU), a debilitating dermatological condition. However, many patients respond incompletely, and up-dosing sgAHs up to four-fold their conventional dose is recommended for disease control. Many physicians refrain from up-dosing due to a paucity of efficacy and safety data, instead adding a second antihistamine or an immunomodulator. With the aim of addressing this knowledge gap, we conducted a literature review to highlight efficacy and safety data on up-dosed sgAHs. We conducted a comprehensive search of the literature across multiple databases (PubMed, EMBASE, MEDLINE and Google scholar) using the keywords (alone and in combination) and MeSH items as well as non-MeSH terms such as "chronic spontaneous urticaria", "chronic idiopathic urticaria", AND "updosing", "second-generation anti-histamines", "cetirizine", "fexofenadine", "levocetirizine", "desloratadine", "ebastine", "bilastine", and "rupatadine". Our review suggests bilastine, fexofenadine, levocetirizine, and cetirizine are recommended for up-dosing in non-responsive patients with CSU (Grade A recommendation), while desloratadine and ebastine can be recommended (Grade B recommendation). Among those with Grade A recommendation, bilastine and levocetirizine may be up-dosed safely to four times, while fexofenadine has been studied at three times the conventional dose. None of the drugs showed any dose-dependent increase of adverse effects; however, cetirizine up-dosing may increase the risk of dose-related sedation. There were no reports of systemic complications, including cardiotoxicity, at higher than licensed doses of these drugs. Only cetirizine and rupatadine up-dosing have been documented to be effective and safe in children, while there is lack of data on geriatric patients and pregnant or lactating females.