There is a growing interest in the design and engineering of operational biofuel cells that can be implanted. This review highlights the recent progress in the electrochemistry of biofuel cell technologies, but with a particular emphasis on the medical and physiological aspects that impact the biocompatibility of biofuel cells operating inside a living body. We discuss the challenge of supplying power to implantable medical devices, with regard to the limitations of lithium battery technology and why implantable biofuel cells can be a promising alternative to provide the levels of power required for medical devices. In addition to the challenge of designing a biofuel cell that provides a stable level of sufficient power, the review highlights the biocompatibility and biofouling problems of implanting a biofuel cell that have a major impact on the availability of the substrates inside body that provide fuel for the biofuel cell. These physiological challenges and associated ethical considerations are essential to consider for biofuel cells that are designed to be implanted for long-term operation inside a living animal and eventually to human clinical applications.