As derivatives of extracted triglycerides from natural resources, fatty acid alkyl esters (FAAE) are interesting base oleochemicals for the development of food additives, pharmaceutics and fine chemicals. In 2016, the global oleochemical market size was estimated at 20.2 billion USD with expected compound annual growth rate (CAGR) growth of 5.2% in the period of 2018 to 2025. Although there are significant market opportunities, prominent challenges in their large-scale separation into individual compounds of high purity hamper their current use. The major challenge is to isolate the FAAE without the risk of initiating degradation reactions. Despite the enormous potential of FAAE, a clear overview of current research on the fractionation and purification of this type of oil derivatives is missing. Moreover, separation efficiencies and therefore the upscaling possibilities of the applied technologies are not always consistently mentioned in literature. Therefore, this review focuses on the key opportunities and challenges in the versatile field of fractionation of FAAE in view of efficiency and possible upscaling processes. Oleochemicals are an important type of oil derivatives and insight into new implementation opportunities in the present market is of interest for both academia and industry. A critical overview of the available fractionation research performed in the last decade will provide the reader with clear information on large-scale implementation possibilities, technology readiness levels and scientific challenges.