The active site of an enzyme is surrounded by a fluctuating environment of protein and solvent conformational states, and a realistic calculation of chemical reaction rates and kinetic isotope effects of enzyme-catalyzed reactions must take account of this environmental diversity. Ensemble-averaged variational transition state theory with multidimensional tunneling (EA-VTST/MT) was developed as a way to carry out such calculations. This theory incorporates ensemble averaging, quantized vibrational energies, energy, tunneling, and recrossing of transition state dividing surfaces in a systematic way. It has been applied successfully to a number of hydrogen-, proton-, and hydride-transfer reactions. The theory also exposes the set of effects that should be considered in reliable rate constants calculations.