| Summary: | <i>Yarrowia lipolytica</i> has been a valuable biotechnological workhorse for the production of commercially important biochemicals for over 70 years. The knowledge gained so far on the native biosynthetic pathways, as well as the availability of numerous systems and synthetic biology tools, enabled not only the regulation and the redesign of the existing metabolic pathways, but also the introduction of novel synthetic ones; further consolidating the position of the yeast in industrial biotechnology. However, for the development of competitive and sustainable biotechnological production processes, bioengineering should be reinforced by bioprocess optimization strategies. Although there are many published reviews on the bioconversion of various carbon sources to value-added products by <i>Yarrowia lipolytica</i>, fewer works have focused on reviewing up-to-date strain, medium, and process engineering strategies with an aim to emphasize the significance of integrated engineering approaches. The ultimate goal of this work is to summarize the necessary knowledge and inspire novel routes to manipulate at a systems level the yeast biosynthetic machineries by combining strain and bioprocess engineering. Due to the increasing surplus of biodiesel-derived waste glycerol and the favored glycerol-utilization metabolic pathways of <i>Y. lipolytica</i> over other carbon sources, the present review focuses on pure and crude glycerol-based biomanufacturing.
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