The combination of chemometrics and chromatography is a broad area of research. Analytical chemists are continually developing and applying better chemical separation methods combined with more powerful tools for extracting useful information from the data, as is the role of chemometrics. Within the wide array of published chemometrics research, there have been numerous investigations into the use of chemometric techniques for quantitative or qualitative analysis of chromatographic and electrophoretic data. Although there are many examples of chemometric techniques applied to onedimensional (1-D) separations, this chapter will focus on applications of chemometrics with comprehensive two-dimensional (2-D) separations. Chemometrics and 2-D separations can, independently, offer vast selectivity enhancements over conventional 1D analytical separations and traditional peak identification and quantification methods. These methods can also be used to reduce sample run times. Thus, the combination of comprehensive 2-D separations with chemometrics represents the development of a new and powerful tool in the analysis of complex mixtures. Applications of chemometrics to 1-D separations will be reviewed briefly in Section III in order to put this exciting area of research into context with the issues and advantages provided by 2-D separations.