In healthy livers, hepatocytes exhibit features of epithelial cells because they are polarized and adherent to each other. However, unlike epithelial cells in other tissues, healthy hepatocytes lack a basement membrane. Hence, healthy, mature hepatocytes are not physically separated from the adjacent stroma and hepatic stellate cells that reside in the space of Disse, sandwiched between the hepatic epithelia and fenestrated endothelial cells that line hepatic sinusoids. Indeed, because the sinusoids themselves also lack a typical basement membrane, endothelial cells, hepatic stellate cells, and hepatocytes all coexist within the same mesenchyme. During hepatocarcinogenesis, genetic events that enhance the migratory capabilities of hepatocytes may occur, and the normal absence of membrane barriers to physically separate hepatocytes from the hepatic sinusoids permits easy entry of motile neoplastic hepatocytes into the vascular system. The current study by Chen et al. (4) delineates a mechanism by which malignant hepatocytes become more motile and invasive. Namely, amplification of CDH1L results in induction of ARHGEF9 and resultant activation of the small GTP-binding protein Cdc42. Cdc42-GTP orchestrates various events, including reorganization of cytoskeletal elements that permit neoplastic hepatocytes to migrate away from neighboring epithelial cells, move through the space of Disse, invade neighboring vascular spaces, and be swept along with the blood flow to other parts of the hepatic lobule and/or out of the liver to extrahepatic sites.