Determining the factors that influence the metabolisms of respiring microorganisms is central to understanding the roles that microbes play in altering their geochemical environments, and the effect of environment on the distribution of microbial populations. We have developed a quantitative description of microbial respiration that accounts for both kinetic and thermodynamic effects. Using the model, we consider how the concentrations of substrates and metabolic products serve to regulate microbial respiration. We discover that the commonly observed hyperbolic dependence of microbial activity on substrate concentration arises within the electron transport chain from the interaction of enzyme cofactors with respiratory enzymes. Such a view differs from the traditional explanation, which attributes this affect to the strength of binding between enzyme and substrate. In an effect not considered in many current theories, we show that the accumulation of metabolic products can be expected to strongly inhibit microbial activity. Finally, we emphasize the impact on microbial populations of energy availability in the environment. Competition for energy resources favors microbes that can extract the most energy from the environment per unit time. This competitive pressure leads to the hierarchy of terminal electron accepting processes observed in nature. In the Middendorf aquifer of South Carolina, for example, the distribution along the flow path of electron accepting species reflects a general decrease in energy availability, which gives rise to the aquifer’s zonation in redox potential and microbial populations.