Mass spectrometry (MS)-based top-down proteomics (TDP) characterizes proteoforms in cells, tissues, and biological fluids (e.g., human plasma) to better our understanding of protein function and to discover new protein biomarkers for disease diagnosis and therapeutic development. Separations of proteoforms with high peak capacity are needed due to the high complexity of biological samples. Capillary electrophoresis (CE)-MS has been recognized as a powerful analytical tool for protein analysis since the 1980s owing to its high separation efficiency and sensitivity of CE-MS for proteoforms. Here, we review benefits of CE-MS for advancing TDP, challenges and solutions of the method, and the main research areas in which CE-MS-based TDP can make significant contributions. We provide a brief perspective of CE-MS-based TDP moving forward.