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Abstract Soil microbial communities play a pivotal role in controlling soil carbon cycling and its climate feedback. Accurately predicting microbial respiration in soils has been challenged by the intricate resource heterogeneity of soil systems. This makes it difficult to formulate mathematical expressions for carbon fluxes at the soil bulk scale which are fundamental for soil carbon models. Recent advances in characterizing and modeling soil heterogeneity are promising. Yet they have been independent of soil structure characterizations, hence increasing the number of empirical parameters needed to model microbial processes. Soil structure, intended as the aggregate and pore size distributions, is, in fact, a key contributor to soil organization and heterogeneity and is related to the presence of microsites and associated environmental conditions in which microbial communities are active. In this study, we present a theoretical framework that accounts for the effects of microsites heterogeneity on microbial activity by explicitly linking heterogeneity to the distribution of aggregate sizes and their resources. From the soil aggregate size distribution, we derive a mathematical expression for heterotrophic respiration that accounts for soil biogeochemical heterogeneity through measurable biophysical parameters. The expression readily illustrates how various soil heterogeneity scenarios impact respiration rates. In particular, we compare heterogeneous with homogeneous scenarios for the same total carbon substrate and microbial biomass and identify the conditions under which respiration in heterogeneous soils (soils having non-uniform distribution of carbon substrate and microbial biomass carbon across different aggregate size classes) differs from homogeneous soils (soils having uniform distribution of carbon substrate and microbial biomass carbon across different aggregate size classes). The proposed framework may allow a simplified representation of dynamic microbial processes in soil carbon models across different land uses and land covers, key factors affecting soil structure.