Polysaccharide-K (PSK, Krestin) is one of the most commonly used medicinal mushroom extracts with a long history as an additive in cancer therapy in Asia, especially in Japan. PSK has a documented anti-tumor activity both in vitro and in vitro, in various types of cancers, including colorectal, gastric, breast, liver, pancreatic, and lung cancer. Despite PSK having been studied for about 40 years as an immune modulator and biological response modifier, the mechanisms of action by PSK have not yet been clearly and completely elucidated. This review aims to provide an up-to-date account for the effects of PSK in cancer with the hope of thereby providing an increased understanding of the molecular mechanisms of PSK and also its potential as an additive in modern cancer therapy.