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 center dot center dot center dot H contacts and contributions of such interactions to protein-ligand binding C, affinity. Notably, F center dot center dot center dot H interactions in biomolecules exhibit a remarkably different behavior as compared to three other kinds of X center dot center dot center dot H (X = Cl, Br, I) interactions, which has been rationalized by means of A initio calculations using simple model systems. The C-X center dot center dot center dot 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 biomolecullar systems, C-X center dot center dot center dot H contacts are recognized as secondary interaction contributions to C-X center dot center dot center dot 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.