Significant advances have been made in recent years discovering new electrocatalysts and developing a fundamental understanding of electrochemical CO2 reduction processes. This field has progressed to the point that efforts can now focus on translating this knowledge toward the development of practical CO2 electrolyzers, which have the potential to replace conventional petrochemical processes as a sustainable route to produce fuels and chemicals. In this Perspective, we take a critical look at the progress in incorporating electrochemical CO2 reduction catalysts into practical device architectures that operate using vapor-phase CO2 reactants, thereby overcoming intrinsic limitations of aqueous-based systems. Performance comparison is made between state-of-the-art CO2 electrolyzers and commercial H2O electrolyzers—a well-established technology that provides realistic performance targets. Beyond just higher rates, vapor-fed reactors represent new paradigms for unprecedented control of local reaction conditions, and we provide a perspective on the challenges and opportunities for generating fundamental knowledge and achieving technological progress toward the development of practical CO2 electrolyzers.