The ability of 15 sesquiterpenoids containing an unsaturated dialdehyde functionality to damage cellular membranes, measured as the induction of ATP leakage in ELD cells, has been investigated. In spite of the structural similarities of this class of compounds, large differences in potency were noted. The results from the ATP leakage assay were correlated (by the multivariate PLS method) with a number of structural descriptors, such as intra-atomic distances and angles, atomic charges, and lipophilicity, to obtain quantitative structure-activity relationships. A component consisting of the distance and the dihedral angle between the two aldehyde groups, the dipole moment, the lipophilicity, and the chemical stability, was found to be correlated with the activity in the ATP leakage assay. This indicates that the activity of the unsaturated dialdehydes depends on their accumulation in lipophilic parts of a cell (e.g. the membranes), the way they orient themselves in a membrane, and their chemical reactivity towards proteins associated with a membrane.