There is an increasing interest in identifying effective and safe constituents from medicinal mushrooms for cancer prevention and treatment. Ganoderma lucidum has been used for this purpose, which is given as a single agent, or in combination with herbs or synthetic chemotherapeutic agents. Various polysaccharides (in particular β-D-glucans and glycoproteins) and triterpenoids have been found to be the major active constituents responsible for the chemopreventive and tumoricidal activity of G. lucidum. These compounds exerted promising cancer preventive and anticancer activity in animal (mouse and rat) studies. However, randomized, placebo-controlled, and multicenter clinical studies using G. lucidum have rarely been reported. In a randomized, placebo-controlled clinical study, 38 (26.6%) of 143 cancer patients had stable disease for 12 weeks or more (range, 12−50 weeks) when treated with Ganoply (a G. lucidum polysaccharide extract) orally at 1800 mg three times daily for 12 weeks. Palliative effects on cancer-related symptoms, such as sweating and insomnia, have been observed in many patients. Ganopoly was well tolerated, with five moderate adverse events recorded. These initial findings indicate that G. lucidum may represent a practical and promising approach for cancer prevention and cancer treatment. Further studies are required to establish the relationship between G. lucidum intake dose and cancer risks and to investigate the efficacy and safety when used alone or in combination with chemotherapy.