CE coupled MS (CE-MS) has become an increasingly employed technology in proteome analysis with focus on the identification of biomarker peptides in clinical proteomics. In this review, we will cover technical aspects of CE-MS coupling and highlight the improvements made in the last few years. We examine CE-MS from an application point of view, and evaluate its merits and vices for biomarker discovery and clinical applications. We discus the principal theoretical and practical obstacles encountered when employing CE-MS (and most other proteomic technologies) for the analysis of body fluids for biomarker discovery. We will present several examples of a successful application of CE-MS for biomarker discovery, implications for disease diagnosis, prognosis, and therapy evaluation, and will discuss current challenges and possible future improvements.