Hepatoma-derived growth factor (HDGF) was purified and cloned from a human hepatocellular carcinoma (HCC) cell line, which proliferated in serum-free chemically-defined medium. HDGF and five other HDGF-related proteins belong to a new protein family with a significant homology in their amino terminus. HDGF is a nuclear targeted mitogen containing nuclear localization signals, and the ability to translocate to the nucleus plays an important role in the mitogenic activity. On the other hand, exogenously supplied HDGF stimulates the cellular proliferation through MAP kinase activation. A putative candidate receptor for HDGF has been identified. HDGF is a unique and interesting factor which exerts its function via a signal pathway from cell membrane binding and its direct action on DNA after nuclear translocation. HDGF is strongly expressed in cancer cells, which originate from the liver, lung, colon, stomach and pancreas. HDGF also shows anti-apoptotic activity. In a mouse hepatocarcinogenesis model, HDGF is induced in the liver tissue at an early stage before the development of liver tumors. Exogenously supplied and endogenously over-expressed HDGF enhances the proliferation of cancer cells. HDGF-over-expressing cells generate tumors and enhance tumor growth in nude mice. HDGF also stimulates cell migration and tubule formation as well as the proliferation of human endothelial cells, and plays important roles in neovascular formation, including tumor angiogenesis. HDGF induces tumorigenesis in vivo through both its direct angiogenic activity and the induction of VEGF. The down-regulation of endogenous HDGF in cancer cells suppresses their proliferation, invasive activity and anchorage-independent growth in soft agar in vitro. The increased expression of HDGF is associated with more malignant potential for cancer progression. HDGF may be a useful prognostic factor for disease-free and/or overall survivals in patients who have undergone a resection of HCC, non-small cell lung cancer, gastric cancer, esophageal cancer, pancreatic cancer and gastrointestinal stromal tumor. This review will describe the current knowledge about the pathophysiological roles of HDGF in tumor growth, and its possible clinical utility in cancer regulation.