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Urticaria is a skin lesion characterized by a central swelling area of varying sizes, usually surrounded by erythema and accompanied by itching or a burning sensation. Recurrence for at least six weeks characterizes chronic urticaria, a condition that has no cure, only treatment to minimize symptoms. The available pharmacological therapies show variable success and do not regulate the inflammatory balance of the skin in the long term. Therefore, it is essential to evaluate treatment possibilities to seek new symptom management approaches. In this regard, this study addresses the currently available therapies, linking the disease's pathophysiology with purinergic signaling to identify new therapeutic possibilities. In this respect, extracellular ATP is related to mast cells degranulation in the skin, which affects urticaria. Considering other dermatological diseases that present an inflammatory response, the purinergic receptor P2X7 is related to inflammation in several pathological skin conditions, such as psoriasis, dermatitis and pruritus. P2X7 engagement also contributes to ATP-mediated mast cell degranulation. Therefore, evaluating the expression of purinergic receptors in the skin of patients with chronic spontaneous urticaria, along with ATP levels in urticarial lesions, may help elucidate the therapeutic potential of targeting this purinergic pathway. KEY MESSAGES: Many patients are refractory to licensed therapies of H1antihistamines and omalizumab. Cyclosporine and other immunosuppressants are studied for refractory patients. Probiotics as adjuncts to antihistamines are studied to reduce symptoms. P2X7 receptor links to inflammatory skin diseases and may offer new therapy approach.