There has been extensive structural and mechanistic investigation of iridoid synthase (ISY),3 the enzyme that creates this core bicyclic scaffold (Fig. 1), from the medicinal plant Madagascar periwinkle (Catharanthus roseus). These studies have revealed how the iridoid core cyclizes after transfer of a hydride from NADPH to the linear precursor 8-oxogeranial (11–13). In Catharanthus, only iridoids with the stereocenter C7 fixed in the S configuration and the ring fusion in the configuration commonly referred to as “cis–trans” (Fig. 1; hydrogens cis at C4a and C7a and trans at C7a and C7) are observed. The hydride transfer step catalyzed by iridoid synthase accounts for the configuration at C7. “Epi-iridoids” with an inverted methyl group at C7 (e.g. antirrhinoside, catalpol, epi-loganic acid, penstemoside) are common in Plantaginaceae (10, 14). A detailed biosynthetic hypothesis for 7-epi-iridoids has been developed in Plantaginaceae based on deuterium labeling. Only deuterated 7-epi-deoxyloganic acid, but not deoxyloganic acid, was incorporated into iridoids in Scrophularia racemosa, Plantago major, and Buddleja davidii. Although the C7 stereocenter is removed and reinstalled in later biosynthetic steps, these studies strongly suggest that 7-epi-nepetalactol (C7-R) is the productive iridoid intermediate (Fig. 1) (15–18). We hypothesize that an epi-iridoid synthase that reduces C7 of 8-oxogeranial with R preference is involved in the biosynthetic pathway. We searched for a homologue of iridoid synthase that performs the R-selective reduction of the iridoid precursor 8-oxogeranial. Here we identify the iridoid synthase from A. majus (AmISY), which displays epi-iridoid synthase activity.