The leading cause of liver failure in the US is drug-induced liver toxicity. Currently there is an absence of a good model of human drug metabolism in the liver, which poses one of the biggest road blocks to testing drug-induced liver toxicity prior to clinical studies or release of the drug into the market. We are using human embryonic stem (hES) cells to develop a clinically predictive drug screening system that should allow earlier detection of drug-induced liver toxicity, thus decreasing drug costs, decreasing the scale of pre-clinical animal testing, and increasing drug safety. There are two arms to this work. The first is to engineer a new hES cell line that attaches a fluorescent molecule to a protein found in mature liver cells. To date we have completed the genetic molecules necessary for development of this cell line, and we are currently using these molecules to generate the engineered hES cell line. The second arm is to test new methods to enhance the maturation of hES-derived liver cells, since current hES protocols only yield immature liver cells. As part of this approach, we are testing a novel 3D culture system that has already been shown to improve maturation of other cell types, such as heart cells and fresh liver cells from humans. By combining our new hES cell line with improved protocols for generating mature hES-derived liver cells, we will have a powerful system not only for screening drugs for potential liver toxicity effects but also for improving protocols for transplantation and regenerative medicine purposes. We plan to openly share this new cell line with the scientific community under standard licensing agreements so that rapid progress can be made in both these areas.