The combination of capillary electrophoresis and mass spectrometry (CE-MS) has become an important tool within the group of high performance analytical techniques. A key aspect of this hyphenated technique is selection of the appropriate interface connecting the separation part (CE) with the detector (MS). Although many different approaches for CE-MS interfacing have been presented in the literature, the most widely used and, up to now, only commercially available option is the coaxial sheath flow interface. Primary strong points of this interface are its robustness, ease of handling, and the fact that the addition of a sheath liquid also may allow the use of normally MS-incompatible background electrolytes for CE. On the other hand, the use of sheath flow leads to a dilution of the CE effluent, which can compromise sensitivity. In the present contribution, we describe a novel approach introducing an additional functionality of the sheath liquid. Commonly, the sheath flow is introduced mainly to ensure a stable electrospray and also by the addition of small amounts of acidic or basic components enhance the ionization of the analytes. A further possibility is the use of the sheath liquid for chemical reactions - allowing the quasi post-capillary “derivatization” of the analytes. Some simple approaches for such “in-sheath flow” reactions include deuterium exchange, use of stable free radicals for free radical assay and the formation of covalent complexes to simultaneously increase the molecular weight of the analyte and change the charge state of the ion.