C-fiber afferents in the airways are in close contact with mast cells and are activated both upon allergic reactions and by inhalation of irritants such as capsaicin and cigarette smoke. This evokes both protective reflexes such as cough as well as local release of tachykinins and calcitonin gene-related peptide (CGRP) with subsequent actions on blood vessels (vasodilatation and plasma protein extravasation) and bronchial smooth muscle (bronchoconstriction). After capsaicin pretreatment when peptides have been depleted from the sensory nerves, there is a marked reduction of the vasodilatatory response upon allergen challenge and the protein extravasation evoked by cigarette smoke. Conversely, chronic cigarette smoke exposure is accompanied by increased coughing to capsaicin challenge. Furthermore, aerosol immunization and chronic smoke exposure are both associated with elevated tissue levels of CGRP, suggesting upregulation of C-fiber function and peptide synthesis, which may contribute to airway hyperreactivity.