The ability to observe the changes that occur at an enzyme active site during electrocatalysis can provide very valuable information for understanding the mechanism and ultimately aid in catalyst design. Herein, we discuss the development of X-ray absorption spectroscopy (XAS) in combination with electrochemistry for operando studies of enzymatic systems. XAS has had a long history of enabling geometric and electronic structural insights into the catalytic active sites of enzymes, however, XAS combined with electrochemistry (XA-SEC) has been exceedingly rare in bioinorganic applications. Herein, we discuss the challenges and opportunities of applying operando XAS to enzymatic electrocatalysts. The challenges due to the low concentration of the photoabsorber and the instability of the protein in the X-ray beam are discussed. Methods for immobilizing enzymes on the electrodes, while maintaining full redox control are highlighted. A case study of combined XAS and electrochemistry applied to a [NiFe] hydrogenase is presented. By entrapping the [NiFe] hydrogenase in a redox polymer, relatively high protein concentrations can be achieved on the electrode surface, while maintaining redox control. Overall, it is demonstrated that the experiments are feasible, but require precise redox control over the majority of the absorber atoms and careful controls to discriminate between electrochemically-driven changes and beam damage. Opportunities for future applications are discussed.