In this work, we report a detailed study of the microsolvation of anionic ibuprofen, Ibu−. Stochastic explorations of the configurational spaces for the interactions of Ibu− with up to three water molecules at the DFT level lead to very rich and complex potential energy surfaces. Our results suggest that instead of only one preponderant structure, a collection of isomers with very similar energies would have significant contributions to the properties of the solvated drug. One of these properties is the shift on the vibrational frequencies of the asymmetric stretching band of the carboxylate group in hydrated Ibu− with respect to the anhydrous drug, whose experimental values are nicely reproduced using the weighted contribution of the structures. We found at least three types of stabilizing interactions, including conventional \documentclass[12pt]{minimal}\begin{document}${\rm CO}_2^-\cdots$\end{document} CO 2−⋯H2O, H2O⋯H2O charge assisted hydrogen bonds (HBs), and less common H2O⋯H–C and H2O⋯π interactions. Biological water molecules, those in direct contact with Ibu−, prefer to cluster around the carboxylate oxygen atoms via cyclic or bridged charge assisted hydrogen bonds. Many of those interactions are strongly affected by the formal carboxylate charge, resulting in “enhanced” HBs with increased strengths and degree of covalency. We found striking similarities between this case and the microsolvation of dymethylphosphate, which lead us to hypothesize that since microsolvation of phosphatidylcholine depends mainly on the formal charge of its ionic \documentclass[12pt]{minimal}\begin{document}${\rm PO}_2^-$\end{document} PO 2− group in the polar head, then microsolvation of anionic ibuprofen and interactions of water molecules with eukaryotic cell membranes are governed by the same types of physical interactions.