A key aim of using a metabolomics approach is to obtain (ultimately) an answer to a well-defined biological question. To this end, state-of-the-art analytical separation techniques are currently used for the reliable profiling of (endogenous) metabolites in a wide range of biological samples. Within metabolomics, capillary electrophoresis–mass spectrometry (CE-MS) has become a very strong analytical tool for the selective profiling of polar and charged metabolites. In CE, compounds are separated according to their charge-to-size ratio and, therefore, the separation mechanism of this approach is fundamentally different from chromatographic-based separation techniques. As such, CE-MS provides complementary information on the metabolic composition of biological samples. In this chapter, the utility of CE and CE-MS for the analysis of (highly) polar and charged metabolites is described from a historical perspective. Attention is devoted to some research works from a few decades ago in which the value of CE for the selective analysis of a few (endogenous) metabolites in human body fluids was demonstrated. Then, seminal research works on the development of CE-MS methods for targeted and non-targeted metabolomics studies are discussed. Finally, the current situation of CE-MS in metabolomics is considered and a view on where this approach may head to is provided.