Chronic spontaneous urticaria (CSU) is a common disorder with a prevalence of 1% that is characterized by recurrent wheals, angioedema, or both. CSU is self-limited but in many patients symptoms recur for several years and can be refractory to standard therapies. In this review, we present an illustrative case of a female patient with CSU who, despite taking 15 antihistamines a day in addition to a number of second-line therapies, continued to be refractory to treatment. However, once we initiated subcutaneous treatment with omalizumab 300 mg every 4 weeks, she experienced rapid relief of her CSU symptoms. Through this case, we present a review of the relevant issues, including the efficacy of laboratory tests to identify the cause of a patient's CSU, the association between CSU and thyroid disease and its relevance to treatment options, the recommendation to increase antihistamine dose up to fourfold and possible adverse events associated with this treatment option. We also include a discussion of the use of second-line therapies as well as omalizumab in refractory CSU patients.