The effects of urticaria are predominantly mediated by histamine release; therefore, H1-antihistamines are the mainstay of treatment. Second-generation H1-antihistamines, compared with their first-generation counterparts, have demonstrated improved peripheral H1-receptor selectivity and decreased lipophilicity (which minimizes CNS adverse effects), and antiallergic properties in addition to being histamine inverse agonists. Evidence of clinical efficacy and tolerability of second-generation H1-antihistamines available in the US for the treatment of chronic urticaria (CU) was analyzed using the GRADE system to develop the strength of recommendations for particular therapies. The evidence for the safety and efficacy of the majority of second-generation H1-antihistamines available in the US is of high quality and leads to a strong recommendation for their use in CU. There is a limited amount of data of variable quality comparing the efficacy between various second-generation H1-antihistamines in CU leading to weak recommendations for using cetirizine over fexofenadine and levocetirizine over desloratadine. Limited data of variable quality exist for the efficacy of higher doses of second-generation H1-antihistamines in CU patients not responsive to standard doses. These limited data lead to a strong recommendation that higher than recommended doses of fexofenadine do not offer greater efficacy in control of CU and a weak recommendation that higher doses of levocetirizine and desloratadine are more effective in CU unresponsive to standard doses. More studies of higher quality are required to make any firm recommendations regarding second-generation H1-antihistamines in the treatment of physical urticarias. All second-generation H1-antihistamines appear to be very well tolerated in CU patients, with rare reports of adverse effects. Due to the relatively large gaps in the quantity and quality of evidence, particularly for choice of H1-antihistamines, use of higher doses, and use in physical urticarias, greater emphasis in management decisions should be based on the risk/benefit ratio and the patient's personal values and preferences (including cost) in clinical decision making.