Asthma is among the most common occupational diseases with considerable public health and economic costs. Chemicals that induce hypersensitivity in the airways can cause respiratory distress and comorbidities with respiratory infections such as COVID. Robust predictive models for this end point are still elusive due to the lack of an experimental benchmark and the over-reliance of existing in silico tools on structural alerts and structural (vs chemical) similarities. The Computer-Aided Discovery and REdesign (CADRE) platform is a proven strategy for providing robust computational predictions for hazard end points using a tiered hybrid system of expert rules, molecular simulations, and quantum mechanics calculations. The recently developed CADRE model for respiratory sensitization is based on a highly curated data set of structurally diverse chemicals with high-fidelity biological data. The model evaluates absorption kinetics in lung mucosa using Monte Carlo simulations, assigns reactive centers in a molecule and possible biotransformations via expert rules, and determines subsequent reactivity with cell proteins via quantum-mechanics calculations using a multi-tiered regression. The model affords an accuracy above 0.90, with a series of external validations based on literature data in the range of 0.88−0.95. The model is applicable to all lowmolecular-weight organics and can inform not only chemical substitution but also chemical redesign to advance development of safer alternatives.