Hepatoma Derived Growth Factor (HDGF) was originally identified as a secreted mitogen from the human hepatoma cell line Huh-7. Although initially thought to be a cytoplasmic protein, it became clear that HDGF is a nuclear targeted protein containing a canonical bipartite nuclear localization sequence. In the developing vasculature HDGF is highly expressed in the nucleus of smooth muscle and endothelial cells. HDGF expression in smooth muscle in particular, declines after birth in larger arteries only to be re-expressed with vascular injury in cells of the highly proliferative neointima. In addition, levels of HDGF have recently been shown to be elevated in a number of cancers, suggesting a potential role in cancer development. Because of these roles, HDGF is a potential target for drug design. This review will describe current knowledge about the biochemical functioning of the protein and identify potential avenues for drug development.