Recently, various alternatives to batteries, such as microfabricated fuel cell systems, have been proposed for portable power generation. In large-scale power production plants emphasis is placed on energy conversion efficiency. On the other hand, the intrinsic design objective for portable power generation devices is the energy density, i.e., the electrical energy generated from a given mass or volume of device and fuel cartridge. It is plausible to stipulate that an increase in the energy conversion efficiency of a system leads to an increase in energy density, but we demonstrate through theoretical analysis and case studies that the two metrics are not equivalent. In some cases, such as systems with a combination of fuels, maximizing efficiency leads to drastically different design, operation and performance than maximizing energy density. Another interesting observation is that, due to interaction between components, maximal component efficiency does not always imply maximal system efficiency.