Accurate predictions of atmospheric CO2 concentrations depend on our ability to project microbial responses to changing temperature and moisture regimes. Microbial physiology exhibits direct responses to temperature, with associated changes in carbon and nutrient demand. In addition to these direct effects of temperature, microbes’ environments change with temperature in ways that can induce indirect effects. For example, temperature can influence the relative availability of assimilable resources released via exo-enzyme activities, and microbes must cope with these resource changes. Changing moisture regime can either limit or promote diffusion of substrates and exo-enzymes to reaction sites. The changing availability of assimilable resources accompanying these shifts in temperature and moisture may promote microbial populations that can exhibit plastic stoichiometry. Integrated over spatial and temporal scales, these differential responses may result in complex patterns of CO2 fluxes from soils. We invite investigators exploring these and related issues to help predict microbially mediated decay and respiratory loss of CO2.