Airway irritant exposures in the workplace cause sensory irritation symptoms or signs such as nose and throat pain, rhinorrhea, cough, and airway obstruction, and are associated with nonallergic airway hyperresponsiveness. Using toxicity data to derive chemical-specific occupational exposure limits (OELs) is a critical step in protecting worker health. Respiratory irritation is one of the most common critical effects cited in risk assessments supporting OEL values. However, toxicity data capturing airway sensory irritation responses are often not available for chemicals requiring assessment, even when occupational exposure scenarios indicate inhalation as a route of exposure. As a result, many existing OELs may be inadequately protective against airway irritant responses. This highlights a need for hazard identification methods that are economical, ethical, and informative for sensory irritation effects. In this review, existing knowledge regarding mechanisms of irritancy in the airway is integrated into a mechanistic event framework that accommodates the chemical diversity of airway irritants. This framework identifies discrete molecular initiating events and outcome modifiers upstream of sensory irritation responses. These include activation of specific receptors by irritant ligands, as well as lipid peroxidation, oxidative stress, rapid saline changes, and membrane-detergent events that initiate neuroexcitatory and inflammatory processes in airway nerves and tissues. The use of an in vitro predictive assay suite to measure these events may allow for a low-cost, medium-throughput option for screening large numbers of chemicals for sensory irritant hazards, thereby indicating data needs necessary for setting OELs.