Homology modelling of the human microsomal epoxide hydrolase (EH) enzyme based on the fungal (Aspergillus niger) EH crystallographic template is reported. The active site lies in a well-defined, essentially hydrophobic, pocket within the overall enzyme structure. Two tyrosine residues, that are conserved in all known mammalian EH sequences, are able to form hydrogen bonds (one per tyrosine residue) with the epoxide oxygen atom on the known EH substrate, styrene oxide. There is also a small hydrophobic cleft, within the active site region, where the phenyl group of styrene oxide can bind, but this appears to be restricted such that the presence of bulky side-chains will render poor substrate status to the incoming epoxide molecule. Quantitative structure–activity relationship (QSAR) studies on a series of low molecular weight epoxides provide useful results which appear to be generally consistent with the human microsomal EH model, and thus may be used predictively for assessing the EH substrate and/or inhibitor status of untested compounds.