Coughing can be both voluntarily induced and involuntarily initiated by activation of vagal afferent nerves innervating the airways and lungs. Centrally, cough is regulated at the level of the brainstem through integration of vagal afferent nerve input by relay neurones in the nucleus tractus solitarius (nTS). Projections to and from the nTS add further complexity to cough regulation, as do the profound influences of psychological and social factors known to regulate cough. Peripherally, both neuronal and non-neuronal elements in the airways regulate the excitability of the vagal afferent nerve terminals regulating cough. These multiple levels of integration and encoding of the cough reflex may render this defensive respiratory response highly susceptible to modulation both by disease processes and through therapeutic intervention.