The importance of water in biological systems has long been recognized in chemistry and biology communities. In this article we describe a new manner by which water affects biomolecular behaviors, called halogen-water-hydrogen bridge (XWH bridge), that is, one hydrogen bonding (H-bonding) in water-mediated H-bond bridge is replaced by halogen bonding (X-bonding). Although behaving similarly to water-mediated H-bond motif, the XWH bridge usually stands in multifurcated forms and possesses stronger directionality. Quantum mechanical analysis on several model and real systems reveals that the XWH bridges are more thermodynamically stable than other water-involved interactions, and this stability is further enhanced by the cooperation of X-bonding and H-bonding. Crystal structure survey clearly demonstrates the significance of XWH bridges in stabilization of biomolecular conformations and in mediation of protein-protein, protein-nucleic acid, and receptor-ligand recognition and binding. These findings shed light into the potential value of XWH bridges in drug design and biological engineering. (C) 2009 Elsevier Inc. All rights reserved.