The liver’s extraordinary ability to regenerate has been known since the myth of Prometheus, but the mechanisms involved are still being discovered. Various small animal models have been used in this quest. Two of the most popular include partial hepatectomy (PHx), in which two-thirds of the liver mass is surgically removed to evoke a massive, immediate stimulus for regeneration, and prolonged exposure to toxins that kill liver cells more gradually, provoking chronic regenerative activity. In either case, multiple types of cells must interact effectively to repopulate the organ with functional mature hepatocytes and thus assure ultimate restoration of healthy liver structure and function. This complexity has confounded efforts to distinguish specific changes that occur in cells that repopulate the hepatocyte compartment from changes in other cell populations, including subpopulations of hepatocytes or hepatocyte precursors that do not become regenerative. In the current issue of the JCI, Wang et al. used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs from repopulating hepatocytes in order to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury imposed by inherent byproducts of tyrosine metabolism. This innovative methodology can potentially be used to design therapeutic strategies for liver regeneration.