Single-chamber fuel cells (SCFC) are ones in which the fuel and oxidizer are premixed, and selective electrode catalysts are used to generate the oxygen partial pressure gradient that in a conventional dual-chamber design is produced by physical separation of the fuel and oxidizer streams. SCFCs have been shown capable of generating power densities above 700 mW/cm2 with appropriate catalysts, making them potentially useful in many applications where the simplicity of a single gas chamber and absence of seals offsets the expected lower efficiency of SCFCs compared to dual-chamber SOFCs.SCFC performance is found to depend sensitively on cell microstructure, geometry, and flow conditions, making experimental optimization tedious. In this paper, we describe recent work focused on developing a quantitative understanding the physical processes responsible for SCFC performance, and the development of an experimentally-validated, physically-based numerical model to allow more rational design and optimization of SCFCs. The use of the model to explore the effects of fuel/oxidizer ratio, anode thickness, and flow configuration is discussed.