Rigorous substrate selectivity is a hallmark of enzyme catalysis. This selectivity is generally ascribed to a thermodynamically favorable process of substrate binding to the enzyme active site based upon complementary physiochemical characteristics, which allows both acquisition and orientation. However, this chemical selectivity is more difficult to rationalize for diminutive molecules that possess too narrow a range of physical characteristics to allow either precise positioning or discrimination between a substrate and an inhibitor. Foremost among these small molecules are dissolved gases such as H2, N2, O2, CO, CO2, NO, N2O, NH3, and CH4 so often encountered in metalloenzyme catalysis. Nevertheless, metalloenzymes have evolved to metabolize these small-molecule substrates with high selectivity and efficiency.The soluble methane monooxygenase enzyme (sMMO) acts upon two of these small molecules, O2 and CH4, to generate methanol as part of the C1 metabolic pathway of methanotrophic organisms. sMMO is capable of oxidizing many alternative hydrocarbon substrates. Remarkably, however, it will preferentially oxidize methane, the substrate with the fewest discriminating physical characteristics and the strongest C-H bond. Early studies led us to broadly attribute this specificity to the formation of a "molecular sieve" in which a methane- and oxygen-sized tunnel provides a size-selective route from bulk solvent to the completely buried sMMO active site. Indeed, recent cryogenic and serial femtosecond ambient temperature crystallographic studies have revealed such a route in sMMO. A detailed study of the sMMO tunnel considered here in the context of small-molecule tunnels identified in other metalloenzymes reveals three discrete characteristics that contribute to substrate selectivity and positioning beyond that which can be provided by the active site itself. Moreover, the dynamic nature of many tunnels allows an exquisite coordination of substrate binding and reaction phases of the catalytic cycle. Here we differentiate between the highly selective molecular tunnel, which allows only the one-dimensional transit of small molecules, and the larger, less-selective channels found in typical enzymes. Methods are described to identify and characterize tunnels as well as to differentiate them from channels. In metalloenzymes which metabolize dissolved gases, we posit that the contribution of tunnels is so great that they should be considered to be extensions of the active site itself. A full understanding of catalysis by these enzymes requires an appreciation of the roles played by tunnels. Such an understanding will also facilitate the use of the enzymes or their synthetic mimics in industrial or pharmaceutical applications.