Lentinula edodes (Berk.) Pegler (shiitake) is an edible mushroom originating from East Asia that is widely cultivated and consumed globally. Medicinal and edible mushrooms have been exploited for centuries in traditional and alternative medicines and oriental therapies to treat ailments. Contemporary research findings have endorsed the health benefits of edible mushrooms. Modern clinical practices in Korea, Japan, and China rely on mushroom-derived extracts and supplements. Mushrooms have been researched for their phytochemistry, nutritional, and medicinal properties. In terms of medicinal effects, mushrooms are consumed by health-conscious consumers worldwide for cancer prevention, combating cardiovascular diseases, blood circulation improvement, immunomodulatory effects, and cholesterol-lowering properties. Some medicinal mushrooms, such as the shiitake mushroom, have been utilized for centuries to treat emotional and physical stress, chronic hepatitis, and gastric ulcers. Shiitake mushrooms exhibit antioxidant, anti-inflammatory, antibacterial, antifungal, anticarcinogenic and immunomodulatory activities. This chapter details the therapeutic benefits of shiitake mushrooms. Important bio-components in shiitake mushrooms include vitamin E, butyric acid, ergosterol, and oleic and linoleic acids, which make shiitake mushrooms an important anti-atherosclerotic agent. These therapeutic benefits have boosted the popularity of shiitake mushrooms as a functional food.