Abstract
Among the different disciplines covered by mass spectrometry, measurement of ^13^C/^12^C isotopic ratio crosses a large section of disciplines from a tool revealing the origin of compounds to more recent approaches such as metabolomics and proteomics. Isotope ratio mass spectrometry (IRMS) and molecular mass spectrometry (MS) are the two most mature techniques for ^13^C isotopic analysis of compounds, respectively, for high and low‐isotopic precision. For the sample introduction, the coupling of gas chromatography (GC) to either IRMS or MS is state of the art technique for targeted isotopic analysis of volatile analytes. However, liquid chromatography (LC) also needs to be considered as a tool for the sample introduction into IRMS or MS for ^13^C isotopic analyses of non‐volatile analytes at natural abundance as well as for ^13^C‐labeled compounds. This review presents the past and the current processes used to perform ^13^C isotopic analysis in combination with LC. It gives particular attention to the combination of LC with IRMS which started in the 1990's with the moving wire transport, then subsequently moved to the chemical reaction interface (CRI) and was made commercially available in 2004 with the wet chemical oxidation interface (LC‐IRMS). The LC‐IRMS method development is also discussed in this review, including the possible approaches for increasing selectivity and efficiency, for example, using a 100% aqueous mobile phase for the LC separation. In addition, applications for measuring ^13^C isotopic enrichments using atmospheric pressure LC‐MS instruments with a quadrupole, a time‐of‐flight, and an ion trap analyzer are also discussed as well as a LC‐ICPMS using a prototype instrument with two quadrupoles. © 2007 Wiley Periodicals, Inc., Mass Spec Rev 26:751–774, 2007