Natural products provide excellent potential leads for drug development because of their chemical diversity and biological functionality. However, the productivity of discovery of new, pharmacologically active natural products has traditionally been low due to inherent difficulties and costs associated with extract dereplication, i.e., isolation, purification and structure elucidation of individual components of plant metabonomes. Thus, traditional approaches (in which structural information is obtained at the end of a lengthy purification process) frequently result in re-isolation of known and trivial natural products. Hyphenation of separation methods with a powerful structure elucidation technique such as high-field NMR allows structural information about extract components to be obtained prior to preparative-scale purification, allowing the isolation efforts to be focused on desired extract constituents. However, traditional HPLC-NMR schemes suffer from sensitivity constraints and limitations related to solvents, since HPLC separations and NMR spectroscopy require different solvents for optimal performance. A novel solution to these problems is provided by HPLC-SPE-NMR, where the SPE interface allows sample concentration as well as solvent change. Examples of the use of HPLC-SPE-NMR as a method of rapid plant extract dereplication will be provided; together with a 600 MHz magnet, the method allows acquisition of high quality 2D NMR data including COSY, gHSQC and gHMBC experiments. Coupled with a mass spectrometer and automatic compound identification, the method constitutes an excellent productivity tool in natural products research and in NMR-based metabonomics.