Supercritical Fluid Chromatography (SFC) has re-emerged as a first-rate technique for purification of candidate drugs in the pharmaceuticalindustry; fuelled by new and improved instrumentation and a rapidly growing interest in the scientific community. SFC is considered much morecomplex and difficult than HPLC by new users but that is largely compensated for by strong advantages such as lower environmental impact andthe much shorter separation times and thus larger production rates. However, there are remaining challenges and difficulties with packed columnSFC, the most studied are those resulting from the compressibility of the mobile phase, leading to the concept that SFC is a ‘rubber variant’of HPLC, where everything considered constant in HPLC, is not in SFC. In this article we will discuss and review, with new and review materialsanother challenge not often addressed in SFC - the fact that sample components cannot be dissolved in the mobile phase, but have to bedissolved in a solvent, and what type of peak distortions that may generate.