Lentinus edodes (shiitake) is a basidiomycete that has been consumed for more than 2000 years because of its nutritional value and health benefits. It has a low lipid content, high fiber content, and a considerable amount of proteins; it also contains B vitamins and minerals in addition to a wide range of functional metabolites including polysaccharides, polysaccharopeptides, lectins, and secondary metabolites with bioactivity, e.g., lentinan, a β-(1-3)-glucan with immunomodulatory activity, among others. Extracts and pure compounds of shiitake exhibit antibacterial, antifungal, cytostatic, antioxidant, anticancer, and immunomodulatory activity. Because of these attributes, different products derived from shiitake are on the market and are sold as dietary supplements. The traditional substrate for shiitake production is oak wood, yet the search for unconventional substrates has intensified over the past three decades. In particular, submerged cultivation of medicinal mushrooms has attracted great interest because it enables greater control of different fermentation factors to obtain products of interest. However, it is necessary to perform in vivo studies to determine the appropriate doses, side effects, and action spectrum of different bioactive compounds and fractions as well as to improve their production in liquid media and to potentiate their activity. We present an updated review of existing studies on the production of biomass and bioactive compounds of L. edodes in liquid culture and on solid fermentation for obtaining secondary mycelia and basidiomata.