On-Line supercritical fluid extraction – supercritical fluid chromatography – mass spectrometry (SFE-SFC-MS) holds with it the promise for more streamlined sample preparation combined with high efficiency separations for myriad applications in food, environmental, forensics, pharmaceutical, and biological sciences. Even so, the wide application base with respect to types of samples and analytes, combined with the multitude of instrumental settings to be optimized, makes method development an initially daunting task. We have been exploring the use of multivariate experimental design approaches, including factorial design and response surface methodologies, to systematically approach the best starting points for new application developments. Much of this work has focused on the use of a wide analyte set, ranging in molecular weight, log P, and pKa; however, some focused work on environmental and forensics matrices has been explored. This presentation will provide a rationale for multivariate optimization to enable the wide application of commercial SFE-SFC-MS technology.