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The hydrogen bond acceptor capability of halogens has long been underappreciated in the field of biology. In this work, we have surveyed structures of protein complexes with halogenated ligands to characterize geometrical preferences of C−X···H contacts and contributions of such interactions to protein−ligand binding affinity. Notably, F···H interactions in biomolecules exhibit a remarkably different behavior as compared to three other kinds of X···H (X = Cl, Br, I) interactions, which has been rationalized by means of ab initio calculations using simple model systems. The C−X···H contacts in biological systems are characterized as weak hydrogen bonding interactions. Furthermore, the electrophile “head on” and nucleophile “side on” interactions of halogens have been extensively investigated through the examination of interactions in protein structures and a two-layer ONIOM-based QM/MM method. In biomolecular systems, C−X···H contacts are recognized as secondary interaction contributions to C−X···O halogen bonds that play important roles in conferring specificity and affinity for halogenated ligands. The results presented here are within the context of their potential applications in drug design, including relevance to the development of accurate force fields for halogens. [ABSTRACT FROM AUTHOR]