Liver disease has long been a heavy health and economic burden worldwide. Once the disease is out of control and progresses to end-stage or acute organ failure, orthotopic liver transplantation (OLT) is the only therapeutic alternative, and it requires appropriate donors and aggressive administration of immunosuppressive drugs. Therefore, hepatocyte transplantation (HT) and bioartificial livers (BALs) have been proposed as effective treatments for acute liver failure (ALF) in clinics. Although human primary hepatocytes (PHs) are an ideal cell source to support these methods, the large demand and superior viability of PH is needed, which restrains its wide usage. Thus, a finding alternative to meet the quantity and quality of hepatocytes is urgent. In this context, human pluripotent stem cells (PSC), which have unlimited proliferative and differential potential, derived hepatocytes are a promising renewable cell source. Recent studies of the differentiation of PSC into hepatocytes has provided evidence that supports their clinical application. In this review, we discuss the recent status and future directions of the potential use of PSC-derived hepatocytes in treating ALF. We also discuss opportunities and challenges of how to promote such strategies in the common applications in clinical treatments.