Brewers’ spent grains constitute a valuable byproduct of the beer industry. They are characterized by a rich nutritional composition consisting of around 70% lignocellulosic fibrous material, 20% proteins, 10% lipids, in addition to vitamins, minerals, amino acids, and phenolic compounds. These spent grains are produced in large amounts all through the year, are cheap, and lack economically feasible applications. Nowadays, 70% of these spent grains are used as animal feed, 10% are used for biogas production, and the remaining 20% are disposed in landfills. Due to the aforementioned facts, alternative uses of the brewers’ spent grains are highly sought-after. In fact, this nutrient-rich industrial by-product makes it a very good candidate for valorization through biotechnological processing, particularly microbial fermentation. After applying the needed pretreatments, using brewers’ spent grains as a substrate in submerged and solid-state fermentation of different microorganisms leads to the production of various value-added compounds such as organic acids, amino acids, volatile fatty acids, enzymes, vitamins, second-generation biofuels and other products.