The ability of aromatic rings to act as acceptors in hydrogen bonds has been demonstrated extensively both by experimental and by theoretical means. Countless examples of D-H...pi (H...pi, D = O, N, C) interactions have been found in the three-dimensional structures of proteins. Much less is known with regard to the occurrence of other possible noncovalent interactions with aromatics in macromolecular structures, those with a geometry that points oxygen lone pairs into the face of a pi system. There has been a growing interest in such lp...pi interactions in recent years, but the binding energies have mostly been studied using small-molecule model systems. We have conducted a survey of lp...pi interactions in crystal structures of DNA, RNA, and proteins and used ab initio calculations to estimate their energies. Our results demonstrate that such interactions are more common in nucleic acids and that significant binding energies only result when the aromatic system is positively polarized, for example, due to protonation of a nucleobase.