Review Philippe Schmitt-Kopplin Moritz Frommberger GSF – National Research Center for Environment and Health, Institute of Ecological Chemistry, Neuherberg, Germany Capillary electrophoresis – mass spectrometry: 15 years of developments and applications Since its introduction in 1987, capillary electrophoresis-mass spectrometry (CE-MS) has developed to a well accepted multidimensional analytical approach complemen- tary and/or competitive to classical MS-hyphenated separation techniques. The three- fold combination of rapid developments of an exceptional separation technique, of selective mass detection possibilities, and of very mild ionization modes first allowed these progresses. This article shows the CE specificities that need to be well con- trolled/known, compared to classical and more routinely used liquid chromatography in the light of its coupling to MS. The major trends and developments over the last 15 years and most of the reviews and applications found in ISI Web of science and publisher databases are presented in a tabulated way. The reader can thus rapidly find existing CE-MS analysis techniques in his field of research and application (foren- sics, environment, bioanalytics, pharmaceutics, and metabolites). Keywords: Atmospheric pressure chemical ionization / Capillary electrophoresis – mass spectrom- etry/ Electrospray ionization / Matrix-assisted laser desorption/ionization / Review DOI 10.1002/elps.200305659 Contents 1 Introduction ........................ 3837 2 Specificity of the separation technique: think CE!........................... 3838 2.1 Hydrodynamic injection: a column dependant injection volume ........... 3839 2.2 Electroosmotic flow: a separation buffer- dependent driving force .............. 3840 2.3 Implications on CE-MS ............... 3841 3 Interfacing CE to MS ................. 3842 3.1 Understanding the ESI technique: a key for comprehensive data interpretation. . . 3842 3.1.1 Some principles of ESI ............... 3842 3.1.2 Development of the interfacing systems: where do we go? .................... 3844 3.1.2.1 Classification of ES interfaces ......... 3844 3.1.2.2 Historical development of the ESI interface ........................... 3845 3.1.2.3 Atmospheric pressure chemical ionization .......................... 3845 3.1.3 Influence of some CE-ESI/MS setups and parameters with the sheath liquid interface ........................... 3847 3.1.3.1 CE system positioning relative to MS instrument ......................... 3847 3.1.3.2 CE capillary positioning at the interface . 3847 3.1.3.3 CE separation conditions ............. 3847 3.1.3.4 Sheath gas conditions ............... 3847 3.1.3.5 Sheath liquid conditions .............. 3848 3.1.3.6 Adduct formation prior/in ESI and their stability ............................ 3849 3.1.3.7 Charge multiplicity of the analytes ...... 3849 4 Applications: statistical evaluation ...... 3850 5 Where do we go? ................... 3851 6 Conclusions ........................ 3852 7 References......................... 3852 8 Addendum ......................... 3859 1 Introduction Our search began with the goal to review all application articles on CE-MS dating from 1996 up to 2003. We rapidly felt excited by reading the “original” literature from the beginning of the 1990s (and before) in the light of “modern” papers and we found it should be very impor- Correspondence: Dr. Philippe Schmitt-Kopplin, GSF – Institut für Ökologische Chemie, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany E-mail: schmitt-kopplin@gsf.de Fax: 149-89-3187-3358 Abbreviations: APCI, atmospheric pressure chemical ionization; CGE, capillary gel electrophoresis; FTICR, fourier transform ion cyclotron MS; IT-reTOF, ion trap-reflectron TOF; MPC, mem- brane preconcentration; NACE, nonaqueous capillary electro- phoresis; PF, partial filling; TITP, transient isotachophoresis Electrophoresis 2003, 24, 3837–3867 3837 CE and CEC  2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim