Ganoderma lucidum (G. lucidum), a basidiomycete white rot fungus, has long been prescribed to prevent and treat various human diseases, particularly in China, Japan, and Korea. Several classes of bioactive substances have been isolated and identified from G. lucidum, such as triterpenoids, polysaccharides, nucleosides, sterols, and alkaloids, among others. This paper examines the potential role of G. lucidum polysaccharide (GLPS) in tumor therapy and the possible mechanisms involved. Both in vitro and in vivo studies suggested that the anti-tumor activities of GLPS are mediated by its immunomodulatory, anti-angiogenic, and cytotoxic effects. GLPS affects immune cells and immune-related cells including B lymphocytes, T lymphocytes, dendritic cells, macrophages, and natural killer cells. In addition, recent data also suggest that GLPS suppresses tumorigenesis or inhibits tumor growth through direct cytotoxic effect and anti-angiogenic actions. However, many questions still need to be answered before both G. lucidum and GLPS can be widely accepted and used as anti-tumor agents.