Antihistamine refractory chronic spontaneous urticaria (CSU) has a prevalence of up to 50%. Anti-immunoglobulin E (IgE) therapies have revolutionized management of CSU, yet refractory cases persist, suggesting a role for biologic agents that impact alternative routes of mast cell stimulation independent of cross-linking at FcεR1. This review addresses anti-IgE and Th2-targeted therapies in the management of CSU. In addition, we explore novel treatments targeting alternative pathways of mast cell activation including MAS-related G protein-coupled receptor-X2 and sialic acid-binding immunoglobulin-like lectin-6, inhibiting intracellular signaling via Bruton’s tyrosine kinase, and disrupting KIT activation by SCF.