Thiols can engage favorably with aromatic rings in S-H/pi interactions, within abiological systems and within proteins. However, the underlying bases for S-H/pi interactions are not well understood. The crystal structure of Boc-L-4-thiolphenylalanine tert-butyl ester revealed crystal organization centered on the interaction of the thiol S-H with the aromatic ring of an adjacent molecule, with a through-space HthiolCaromatic distance of 2.71 angstrom, below the 2.90 Asum of the van der Waals radii of H and C. The nature of this interaction was further examined by DFT calculations, IR spectroscopy, solid-state NMR spectroscopy, and analysis of the Cambridge Structural Database. The S-H/pi interaction was found to be driven significantly by favorable molecular orbital interactions, between an aromatic pi donor orbital and the S-H sigma* acceptor orbital (a pi -> sigma* interaction). For comparison, a structural analysis of O-H/pi interactions and of cation/pi interactions of alkali metal cations with aromatic rings was conducted. Na+ and K+ exhibit a significant preference for the centroid of the aromatic ring and distances near the sum of the van der Waals and ionic radii, as expected for predominantly electrostatic interactions. Li+ deviates substantially from Na+ and K+. The S-H/pi interaction differs from classical cation/pi interactions by the preferential alignment of the S-H sigma* toward the ring carbons and an aromatic pi orbital rather than toward the aromatic centroid. These results describe a potentially broadly applicable approach to understanding the interactions of weakly polar bonds with pi systems.