Mast cells are immune system cells with the most disparate functions, but are also among the least understood. Mast cells are implicated in several known pathological processes, tissue homeostasis, and wound repair. However, they owe their notoriety to allergic diseases, of which they represent the effector cell par excellence. In both allergic and not upper airway pathologies, mast cells play a key role. Exploring the mechanisms through which these cells carry out their physiological and pathological function may help us give a new perspective on existing therapies and identify new ones. A focus will be placed on non-allergic rhinitis, a poorly recognized and often neglected condition with complex management, where the role of the mast cell is crucial in the pathogenetic, clinical, and prognostic aspects.