Macroscopic fungi, mainly higher basidiomycetes and some ascomycetes, are considered medicinal mushrooms and have long been used in different areas due to their pharmaceutically/nutritionally valuable bioactive compounds. However, the low production of these bioactive metabolites considerably limits the utilization of medicinal mushrooms both in commerce and clinical trials. As a result, many attempts, ranging from conventional methods to novel approaches, have been made to improve their production. The novel strategies include conducting omics investigations, constructing genome-scale metabolic models, and metabolic engineering. So far, genomics and the combined use of different omics studies are the most utilized omics analyses in medicinal mushroom research (both with 31% contribution), while metabolomics (with 4% contribution) is the least. This article is the first attempt for reviewing omics investigations in medicinal mushrooms with the ultimate aim of bioactive compound overproduction. In this regard, the role of these studies and systems biology in elucidating biosynthetic pathways of bioactive compounds and their contribution to metabolic engineering will be highlighted. Also, limitations of omics investigations and strategies for overcoming them will be provided in order to facilitate the overproduction of valuable bioactive metabolites in these valuable organisms.
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