ConspectusAs one of the essential pathways to carbon neutrality or carbon negativity, the electrochemical reduction of CO2 offers tremendous prospects for platform chemicals and fuel production. Copper (Cu) is currently the only metal material that is able to reduce CO2 to multicarbon (C2+) products. Despite the fact that copper-based materials have been investigated for decades, we still confront numerous challenges on the path to the fundamental understanding and large-scale deployment of copper-based electrocatalysts for CO2 reduction. For fundamental investigations, it remains a variety of open questions about the CO2 reduction mechanisms. The convoluted C–C coupling pathways and product bifurcation processes confuse the design of efficient catalysts. The active sites of copper-based catalysts remain ambiguous due to surface reconstruction. As for theoretical calculations, the construction of electrolyte–electrode models and the investigation of solvation effects are premature for obtaining confident conclusions. In addition, simple and easily scalable techniques for catalyst synthesis still need to be continuously developed.For practical applications, the CO2 electrolyzer with copper-based materials must be operated with high current densities, high Faradaic efficiencies, high energetic efficiencies, high single-pass conversion rates (high product concentration), and long stability. Nevertheless, due to the intricate nature of electrochemical systems, a high-performance copper-based electrocatalyst alone is not sufficient to meet all of the above commercialization requirements. Therefore, reactor design involving mass transfer enhancement calls for more research input. Based on the above background and the urgency of the net-zero goal, we initiated our research on CO2 electrolysis using copper-based materials with an emphasis on active site identification and mass transfer enhancement.This Account describes our contribution to the field of C2+ products formation. We first discuss the synthesis of copper-based materials with a controlled atomic arrangement and valence states based on neural network-accelerated computational simulations. Using the synthesized catalyst, the selectivity of the target product is improved and the energy consumption of CO2 electrolysis is reduced. Then, we describe the efforts to investigate the reaction mechanisms, such as using first-principles calculations at the atomic level, in situ surface-enhanced vibrational spectroscopies at the micrometer level, and electrochemical kinetics studies at the apparent performance level. We also overview our efforts in the field of reaction system engineering, consisting of a vapor-fed CO2 three-compartment flow cell and a large-scale CO2 membrane electrode assembly, which can increase the reaction rates and single-pass yield. Furthermore, we put forward the main technical obstacles that currently need to be surmounted and provide insights into the commercial application of CO2 electrolysis technology.