Liquid chromatography-nuclear magnetic resonance (LC-NMR) has proven to be a useful technique for the structure elucidation of novel metabolites from pharmaceutical compounds. Proponents of LC-NMR tout the advantage of eliminating the step of a separate chromatographic isolation. However, the advantages of directly coupling NMR and HPLC instrumentation must be weighed against compromises in performance made to each technique to achieve a hyphenated system. While significant advances have been made in LC-NMR technology, a strong case can be made that HPLC purification of metabolites followed by conventional tube NMR is equally useful. It is relatively rare that one approach will be successful and the other not. The fundamental consideration is whether there is sufficient chromatographic expertise in the NMR laboratory to adequately design and execute appropriate experiments such that a pure chromatographic peak will be produced in the hyphenated system. Due to speed and sensitivity differences between NMR spectroscopy and mass spectrometry, liquid chromatography/mass spectrometry (LC/MS) continues to be the front-line approach for the structure elucidation of metabolites.