D-Mannose is an epimer of glucose at the C-2 position and exists in nature as a component of mannan. It has 60 and 86% sweetness than that of sucrose and D-glucose, respectively. Because of its low-calorie and nontoxic features, D-mannose is used widely in food, medicine, cosmetic, and food-additive industries. Besides, it exhibits many physiologic benefits on health: immune system, diabetes mellitus, intestinal diseases, and urinary tract infections. It is used as a starting material to synthesize immunostimulatory agents, anti-tumor agents, vitamins, and D-mannitol. However, D-mannose production using chemical synthesis and plant extraction cannot meet the requirements of the industry. This article presents recent research on the biological production of D-mannose. The physiologic benefits and applications of D-mannose are summarized. Besides, different D-mannose-producing enzymes from various sources are discussed in detail with regard to their biochemical characteristics, catalytic efficiency, and reaction kinetics for D-mannose production. Furthermore, attempts to use enzymatic conversion to produce D-mannose are reviewed.