Multistep enzymatic cascades may be applied to the oxidation of fuels to yield high fuel-efficiency electrochemical energy systems. The ability to structure and pattern anodes at the micron- to nano-scale enables precise placement and orientation of electrodes to maximize utilization of stable intermediates and minimize byproducts. We will present the results of a theoretical analysis of the multistep oxidation of methanol and glucose fuels via enzyme catalysis in which each enzymatic step is resolved to an individual, nanoscale electrode. These results are compared to those obtained for single electrodes with randomly mixed biocatalysts, and to experimental results obtained in a microfluidic biofuel cell.