The chemical structure of low-molecular-weight substances (LMW) that cause occupational asthma (OA) determines their reactivity and hence their OA hazard. LMW agents that can form at least two bonds with native human macromolecules carry a higher OA hazard. Thus bi- or polyfunctional LMW agents such as diisocyanates and aliphatic or cyclic amines, as well as dicarboxylic acid anhydrides and dialdehydes, rank highly among organic LMW substances, while some transition metal ions or their complexes also are OA hazards. More subtle effects arise from diverse reactive groups or unsaturation. Quantitative structure activity relationships show increasing promise in predicting the OA hazard of these LMW substances.