Linking hydrologic interactions with global carbon cycling will reduce the uncertainty associated with scaling-up empirical studies and facilitate the incorporation of terrestrial–aquatic linkages within global and regional change models. Much of the uncertainty in estimates of carbon fluxes associated with precipitation and hydrologic transport results from the extensive spatial and temporal heterogeneity in both intrinsic functioning and anthropogenic modification of hydrological cycles. To better understand this variation we developed a landscape ecological approach to coupled hydrologic–carbon cycling that merges local mechanisms with multiple-scale spatial heterogeneity. This spatially explicit framework is applied to examine variability in hydrologic influences on carbon cycling along a continental scale water availability gradient with an explicit consideration of human sources of variability. Hydrologic variation is an important component of the uncertainty in carbon cycling; accounting for this variation will improve understanding of current conditions and projections of future ecosystem responses to global change.