Supercritical fluid chromatography (SFC) is a fully mature technique and can readily be coupled to mass spectrometers relatively easily. In the last years, supercritical fluid chromatography coupled with mass spectrometry (SFC-MS) has had a great advance in productivity, due to increase in reliability and robustness of both SFC and MS systems, the need to push drug discovery faster, and as a potential solution to old problems unsolved and new problems yet to be encountered. This article will illustrate the role of SFC-MS analysis in drug discovery process.