Pavel Kolkhir, MD, an expert in chronic spontaneous urticaria, teams up with Karen E. Lasser, MD, MPH, a JAMA Senior Editor, to unpack this puzzling condition. They delve into its prevalence and varied symptoms, from itchy wheals to angioedema. The conversation touches on crucial distinctions between autoimmune and autoinflammatory diseases. They also reveal effective treatment strategies, emphasizing the importance of second-generation antihistamines and advanced options like Omalizumab. The impact on patients' quality of life, including psychological challenges, is also explored.