The remarkable regenerative capacity of the adult liver provides a setting to test the functional consequences of grafting human cells generated from pluripotent stem cells. This presentation describes a procedure to differentiate hepatocytes from human embryonic stem and induced pluripotent stem cells using only defined factors. Two cell populations generated in vitro were grafted into the spleen of mice treated with the hepato-toxin carbon tetra-chloride. The population containing few hepatocytes generated few surviving cells that produced low levels of albumin and did not support regeneration of the host liver. The cells enriched in donor hepatocytes efficiently engrafted around the branches of the portal vein, expressed hepatic features for at least 5 weeks. These cells also contributed to the endogenous tissue regeneration and function of the host liver. These results show that the controlled differentiation of hepatocytes from human pluripotent cells provides new approaches to define the mechanisms of tissue regeneration and restore liver function.