Introduction. Stilbene synthase [STS; Enzyme Commission (EC) 2.3.1.95] and chalcone synthase (CHS; EC 2.3.1.74) are members of the type III polyketide synthases (PKSs) and plant-specific enzymes. 1 CHS is widely found in higher plants and plays a key role in the flavonoid biosynthesis by supplying chalcone to downstream enzymes. In contrast, a limited number of plants have STS essential for the synthesis of resveratrol utilized in the stilbenoid biosynthesis. 2 The members of CHS superfamily, including STS, produce linear polyketide intermediates by a common catalytic mechanism where coenzyme A (CoA)-linked starter molecules are iteratively condensed by acetyl units from malonyl-CoA. 3 STS and CHS share around 70% sequence identity without significant deletions and insertions; therefore, the enzymatic mechanism of STS has been considered to be very close to that of CHS. STS and CHS catalyze condensation reactions of pcoumaroyl-CoA and 3 acetyl units from malonyl-CoA, and produce a common linear tetraketide intermediate. In the following cyclization reaction, however, STS and CHS catalyze aldol and Claisen condensation of the tetraketide, resulting in 2 different final products, resveratrol and chalcone, respectively. The crystal structure and molecular mechanism of CHS from Medicago sativa (alfalfa) have recently been reported, 4 but the primary determinant of the cyclization reactions catalyzed by STS and CHS was not clear. More recently, the crystal structure of STS from Pinus silvestris (pine) was reported and provided a framework for understanding the specificity in the cyclization reaction. 5 This report describes the crystal structures of STS from Arachis hypogaea (peanut) in the absence and presence of its final product resveratrol at 2.4 A and 2.9 A, respectively. Detailed structural comparisons of STS from A. hypogaea (peanut STS) with STS from P. silvestris (pine STS) and CHS (alfalfa CHS) evidently revealed common differences between STS and CHS in the local conformation around the active site pocket.