The TOPS-MODE (topological substructural molecular descriptors) approach is used to derive models for understanding the molecular structural contribution to skin sensitization. A data set of 93 compounds was used in the development of the models; 29 new skin sensitization values (EC3) are reported here for the first time. The models developed possess high predictivity and have been validated through the use of cross-validation and external validation sets. The models have enabled the formulation of potential new structural alerts far faster and using less data than typically required by traditional approaches. Structural contributions to skin sensitization for various classes of chemicals are presented on the basis of bond contributions. The models have also been able to identify potential structural alerts for chemicals requiring metabolic activation.