Chronic spontaneous urticaria (CSU) is a heterogeneous, systemic, primarily mast cell-driven disease with sudden appearance of wheals with or without angioedema with pruritus for more than 6 weeks. It affects 0.3%–0.6% of the general population. CSU is a complex immune-mediated disease due to induction of basophil and mast cell degranulation with more than one mechanism of auto-allergy Type I (mediated by specific immunoglobulin E (IgE) targeting auto-allergens as thyroperoxidase, etc.) and auto-immunity Type II (mediated by IgG auto-antibodies binding to alpha-subunit of high affinity IgE receptor [FcERI]) with increased expression of Type II cytokines and activation of coagulation cascade. Pruritus is due to sensory nerve activation by histaminergic pathway (Histamine receptors- H1R and H4R) and histamine-independent pathway (Substance P, Capsacin, and Reactive oxygen species, etc.). The international guidelines on CSU recommend to treat CSU until it is gone. The use of second-generation anti-histamine in effective dose as the first-line treatment and up-dosing of second generation (SgAH) up to four-fold is recommended in treatment-resistant patients. The humanized anti-IgE monoclonal antibody Omalizumab has been shown to have both excellent safety profiles as the only third-line treatment option in anti-histamine-resistant urticaria (approved by United States Food and Drug Administration in August, 2014). However, there are several questions to be answered with reference to the optimal dose, duration, and the rates of long-term remission with omalizumab. Other biologics as Ligelizumab are less well studied but have an important role in the specific type of omalizumab-resistant CSU. In this review, we will summarize the role of omalizumab in anti-histamine resistant CSU.