Poria cocos is an edible mushroom known as “Fuling” in Chinese, which belongs to the fungus family of Polyporaceae. Poria cocos has been used as a Chinese traditional medicine for > 2000 years. Indications for using it include promoting urination, to invigorate the spleen function, and to calm the mind. The bioactive components in Poria cocos include polysaccharides, triterpenoids, fatty acids, sterols, enzymes, etc. Poria cocos polysaccharide (PCP) accounts for 84% by weight among all constituents in the dried sclerotium. Biochemical and pharmacological studies reveal that PCP is the major bioactive component in Poria cocos and has a wide range of biological activities including antitumor, immunomodulation, anti-inflammation, anti-oxidation, anti-aging, anti-hepatitis, anti-diabetes, and anti-hemorrhagic fever effects. As a result, “Poria cocos polysaccharide oral solution” was developed and sold as an over-the-counter health supplement since 1970s. In 2015, “Polysaccharidum of Poria cocos oral solution” was approved as a drug by Chinese Food and Drug Administration (SFDA) for treating multiple types of cancers, hepatitis, and other diseases alone or during chemo- or radiation therapy for cancer patients. In this article, biochemical, preclinical and clinical studies of Poria cocos polysaccharide from 74 independent studies during the past 46 years (1970–2018) based on PubMed, VIP (Chongqing VIP Chinese Scientific Journals Database), CNKI (China National Knowledge Infrastructure), and Wanfang database searches are summarized. The structure, pharmacological effects, clinical efficacy, immune regulatory molecular mechanisms, and toxicity of PCP are deliberated to provide the data basis for PCP to serve as a clinically used antitumor drug.