Capillary electrophoresis combined with mass spectrometry (CE-MS) has been used for several years for the investigation of proteins and peptides as biomarkers for diagnosis and prognosis of diseases. In addition, the technology has recently been introduced to support the stratification of patients in clinical trials and in large clinical studies. In this review, we aim at presenting the development of CE-MS over the last 20 years, by focusing on the clinical potential of proteome and peptidome analysis and highlighting some of the key technical issues and advancements that have been made in this context towards implementation. Based on the reviewed literature, it has become evident that CE-MS is now an accepted tool in clinical application in several disease areas. Apart from a critical overview on the current state-of-the-art in CE-MS, we also indicate the expected developments for potential future use.