Intensive research during the last 15 years on mechanistic understanding of hydrogenases, the key enzyme for H2 transformation in many microorganisms, has authorized the concept of green energy production through H2/O2 enzymatic fuel cells (EFCs), in which enzymes are used as biodegradable and bioavailable biocatalysts. More recently, great effort has been put in the improvement of the interfacial electron transfer process between the enzymes and high surface area conductive materials in order to shift from a proof-of-concept to a usable power device. Herein, we analyze the main issues that have been addressed during the last 5 years to make this breakthrough. After a brief introduction on the structure of hydrogenases and bilirubin oxidases, a widely used enzyme for O2 reduction, we compare their activity with that of platinum. We introduce the first H2/O2 EFCs and discuss their main limitations mainly related to the sensitivity of hydrogenases to O2 and oxidative potentials. We then review the discovery of new enzymes in the biodiversity and the advances in the control of the functional immobilization of these enzymes on electrodes that have permitted to overcome these limitations. We finally present all the reported H2/O2 EFCs, with a critical discussion on the perspectives of such devices.