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An overview of a comprehensive methodology for the design of microfabricated fuel cell systems for portable power generation is presented. The methodology is based on a decomposition into three levels of modeling detail: (i) system-level models for process synthesis, (ii) intermediate-fidelity models for optimization of sizes and operation, and (iii) detailed computational fluid dynamics (CFD) models for geometry improvement. Process synthesis, heat integration, and layout considerations are addressed simultaneously through the use of lumped algebraic models, general enough to be independent of detailed design choices, such as reactor configuration and catalyst choice. At the intermediate-fidelity level, space-distributed models are used, which allow optimization of unit sizes and operation for a given process structure without the need to specify a detailed geometry. Finally, the use of detailed CFD facilitates geometrical improvements as well as the derivation and validation of modeling assumptions that are used in the system-level and intermediate-fidelity models.