The M2 protein of the flu virus forms a proton selective channel that is necessary for viral replication. The channel has a slow rate of conduction but attains near perfect selectivity for protons. Many models have been proposed to explain the mechanism of proton conduction based on whole cell channel recordings and molecular dynamics simulations, but a detailed kinetic analysis of the channel activity has not yet been performed. We obtained detailed conduction vs pH measurements for M2 and a number of its variants using a sensitive and reproducible liposome proton flux assay. The proton transport follows Michaelis-Menten-like kinetics with two saturation steps: one pseudosaturation at pH similar to 5.5, and another full saturation at pH similar to 4. The heart of the mechanism is the pore-lining His37 and Trp41. NMR measurements suggest that histidine and tryptophan act in unison to transport protons down the concentration gradient. The log of apparent K-m derived from the kinetics data matches closely to the histidine pK(a) and correlates with chemical shift perturbation of the Trp41 gate, indicating that histidine protonation and opening of the channel gate are synchronized events. Finally, mutagenesis and structural analysis identified key residues that affect the rate of conduction.