The directed differentiation of human induced pluripotent stem cells (iPSCs) into mature hepatocytes is a major goal of liver research. The approach relies on the recapitulation of developmental processes, and thus a better understanding of what regulates hepatocyte differentiation is essential in order to produce these cells more efficiently and to a greater maturity. In this issue (p. 1764) Stephen Duncan and colleagues identify heat shock protein 90 beta (HSP90β) as a novel regulator of endoderm-to-hepatocyte conversion in differentiating human iPSC cultures. The authors begin the study by conducting a screen for small molecules that modify the activity of master hepatocyte transcription factor HNF4A, identifying 132 candidate ‘hits’. They then focus on the role of molecular chaperone HSP90β and show how it acts at the post-translational level to stabilize HNF4A, thus controlling its half-life and availability. Targeted CRISPR-CAS9 mutations in the gene encoding HSP90 perturbs HSP90β levels, resulting in a dramatic reduction of HNF4A protein levels and reduced expression of HNF4A target genes. Moreover, these experiments reveal that HSP90β is specifically required for endoderm-to-hepatocyte conversion, and not for endoderm commitment generally. This study uncovers a new player in hepatocyte differentiation, and further highlights the utility of an iPSC differentiation platform coupled with chemical screens to uncover novel developmental mechanisms.