In situ x-ray spectroscopies offer a powerful way to understand the electronic structure of the electrode–electrolyte interface under operating conditions. However, most x-ray techniques require vacuum, making it necessary to design spectro-electrochemical cells with a delicate interface to the wet electrochemical environment. The design of the cell often dictates what measurements can be done and which electrochemical processes can be studied. Hence, it is important to pick the right spectro-electrochemical cell for the process of interest. To facilitate this choice, and to highlight the challenges in cell design, we critically review four recent, successful cell designs. Using several case studies, we investigate the opportunities and limitations that arise in practical experiments.