Tremella fuciformis is an edible medicinal mushroom well known as “Yiner” or “Baimuer” in China and has been used as a Chinese herb for many years. T. fuciformis polysaccharide (TFPS) has been identified as a major bioactive component. Different experimental conditions can obtain different TFPS fractions, which makes TFPS a mixture of different polysaccharides with the molecular weight ranging from 5.82 × 105 Da to 3.74 × 106 Da. The monosaccharides detected in TFPS include mannose, xylose, fucose, glucuronic acid, glucose, and galactose. One characterized TFPS chemical structure consists of a linear (1 → 3)-linked α-d-mannose backbone with highly branched β-d-xylose, α-d-fucose and β-d-glucuronic acid as the side chains. TFPS shows multiple physiological and healthy promoting effects including immunomodulation, antitumor, anti-oxidation, anti-aging, hypoglycemic, hypolipidemic, neuroprotection, and other effects. As a result, “Tremella Polysaccharide Enteric-coated Capsules” was approved by Chinese Food and Drug Administration (SFDA) in 2002 for treating cancer patients with leukopenia induced by chemotherapy and radiotherapy. It is also used as adjuvant drug for treating chronic persistent hepatitis and chronic active hepatitis. In this chapter, 113 independent studies involving in biochemical, pharmacological, and clinical studies of TFPS during the past 46 years (1972–2018) on the base of PubMed, CNKI (China National Knowledge Infrastructure) and Wanfang database search are summarized. TFPS shows efficacy for all types of human diseases in the reported clinical studies. The structure, molecular mechanisms of the immunomodulation, antitumor, anti-oxidation, anti-aging, hypoglycemic, hypolipidemic, preclinical and clinical efficacy are discussed to provide a general picture of TFPS as a clinically used drug.