Supercritical fluid chromatography (SFC) has recently experienced renovated impulse from research groups. Its hyphenation to mass spectrometers (MS) proved to be of significant importance in catalysing interest from researchers. In contrast to liquid chromatography (LC), the coupling of SFC-MS requires the use of an interface in order to deal efficiently with the decompression of supercritical CO2 and possible precipitation issues of samples while entering the ionization chamber. The most common SFC-MS interfaces employ an additional sheath pump that reduces sample precipitation. However, there are still issues in dealing with the CO2 decompression phenomenon, with different solutions being given. Matrix effects (MEs) under SFC-MS have proved to be quite different from those generally observed in LC-MS, with ion suppression being the main form of ME. Nonetheless, SFC-MS is capable of reaching comparable sensitivity values to LC-MS, and in some cases performing even better. Several applications have been recently developed for SFC-MS, spacing from the analysis of plant extracts, biological matrices for anti-doping and forensic purposes, as well as highly polar compounds such as carbohydrates and endogenous metabolites.