Rationale: Coughing in humans is typically preceded by a desire (or urge) to cough. The neural circuitry involved in sensing airway irritation and generating the urge-to-cough in humans is essentially unknown. Objectives: The aim of the present study was to use functional brain imaging to describe the supramedullary regions that are activated in humans during capsaicin inhalation. Methods: Experiments were carried out on 10 healthy subjects (5 male, 5 female). Capsaicin doses were individually tailored to evoke a transient and reversible urge-to-cough. Blood oxygen level-dependent (BOLD) functional magnetic resonance measures were collected during repeated 24 second challenges with capsaicin or saline inhalation and subjects were asked to rate the urge-to-cough intensity of each challenge. Measurements and Main Results: Capsaicin inhalation reliably evoked an urge-to-cough which was associated with activations in a variety of brain regions including the insula cortex, anterior-mid cingulate cortex, primary sensory cortex, orbitofrontal cortex, supplementary motor area and cerebellum. Conclusions: These data provide the first insights into the cortical neuronal network involved in sensing airway irritation and modulating coughing in humans.