Proteome analysis using capillary electrophoresis coupled to mass spectrometry (CE-MS) has been used in a number of clinical applications in the past years. The main focus of CE-MS-based studies has been on the investigation of urine, due to the stability of the urinary proteome, ease of collection, and also the low molecular weight range of the urinary proteome, mostly peptides below 30 kDa. The reproducibility of this approach has enabled analysis of over 20000 samples in a comparable way, giving enormous statistical power to any additional study involving this methodological setup. In this article, we review the major technological issues associated with the application of CE-MS in the routine investigation of the urinary proteome for clinical applications. We pinpoint recent developments that may have a chance to improve on the currently used approach, and highlight obstacles that need to be solved. In the second part of the article, we review the recent clinical applications, aiming to highlight relevant issues, and possible future routine applications in clinical diagnosis. In the end, we provide a short outlook, and indicate future developments to be expected, as well as problems that need to be solved to enable routine application of CE-MS in a clinical setting.