The conversion of somatic cells to hepatocytes has fundamentally re-shaped traditional concepts regarding the limited resources for hepatocyte therapy. and requirements for non-physiological manipulations have inhibited their clinical usage. Embryonic stem cells (ESCs) derived from the inner cell mass of mammalian blastocysts have been deemed as ideal candidates for regenerative medicine but have resulted in ethical concerns and incompatibility with the immune system. Adult tissue-derived stem cells which are plentiful without using embryonic materials can be easily extracted but possess innate limitations in stem cell potency and therapeutic potential. Induced pluripotent stem cells (iPSCs) were first generated by Yamanaka and colleagues following the forced expression of four transcription factors (or their transplantation into mice iPSCs can be differentiated into numerous endodermal lineages including hepatocytes [6]. iPSC-derived hepatocyte-like cells (HLCs) can be utilized in disease modeling drug toxicity testing and autologous cell therapies that would avoid immune rejection and enable the correction of genetic defects. In this review we provide a summary of two effective routes including direct reprogramming and indirect reprogramming from somatic cells to hepatocytes and the general potential applications of the resulting hepatocytes. Through these approaches we are advancing toward the goal of achieving a robust mature source of clinically relevant lineages (Figure 1). Figure 1 Promoting a unified field in induced pluripotent stem cell (iPSC)-derived HLCs and achieving a robust mature source of clinically relevant lineages. 2 Reprogramming Somatic Cells to Induced Pluripotent Stem Cell (iPSCs) Most studies have focused on generating iPSCs from somatic cells and have developed multiple routes to improve the efficiency of this process in different cell types. To reprogram efficiently and safely several aspects must be considered. First the reprogramming efficacy varies UNC1215 according to the cell type; thus the choice of cell type may initially determine the transition efficiency; Second reprogramming systems such as viral vectors non-viral vectors direct protein transduction and other new systems exhibit different efficiencies; Third an optimized combination of reprogramming factors can enhance the reprogramming efficiency; Fourth when culturing [5]. can Tmem47 be replaced by can be replaced by and [18]. functionally replaced the three transcription factors and UNC1215 along with [20] suggested that alone is sufficient to mediate the transition from pre-iPSCs to stably reprogrammed cells. Another study demonstrated that is dispensable in the generation of porcine iPSCs [21]. Furthermore over-expression UNC1215 or deletion of some transcription factors can affect reprogramming efficacy in addition to the classical transcription factors. For example over-expression of improves the reprogramming efficiency and facilitates iPSC formation [22]. over-expression in combination with significantly increased the number of alkaline phosphatase-positive goat iPSCs compared to the four transcription factors alone [23]. and play opposite UNC1215 roles in or depletion of greatly facilitates are markers of primary hepatic differentiation and are well-known markers of definitive endoderm. Finally mature hepatocytes are defined by the expression of [38]. At the protein level the production of albumin urea and alpha-1-antitrypsin and the induction of enzymatic activity following treatment with specific inducers and substrates to confirm phase I and II metabolic enzyme activity and their functional abilities are commonly tested in each phase of differentiation [39]. The stable expression and function of and transporters in iPSC-derived HLCs for at least one week allows long-term and extensive studies to be reproducibly performed [40]. These cells maintain the functional activity of many drug-metabolizing enzyme pathways and possess the capacity of active efflux of marker substrates into bile canalicular compartments. The uptake of low-density lipoprotein (LDL) [41] and the uptake and secretion of indocyanine green (ICG) [41] are specific to hepatocytes and thus are used to determine.