We report a critical assessment of the building blocks constituting a general protocol for the study of the structure, strength, and kinetics of hydrogen bridges in large biological systems. The potentialities of self-consistent hybrid approaches for computing reliable potential energy surfaces are described and validated for a number of model systems. Combined discrete-continuum models for studying environmental effects are introduced and applied to some case studies. Finally, some aspects about the role of tunneling are discussed. © 1997 John Wiley & Sons, Inc.