Significance Patient-specific pluripotent stem cells (PSCs) can be derived by two nuclear reprogramming methods: somatic cell nuclear transfer (SCNT) using unfertilized eggs and transcription factor-based reprogramming (i.e., induced pluripotent stem cells, iPSCs). The direct comparison of differentiated cells generated by SCNT and iPSC has yet to be assessed. In this study, we employ cutting-edge technologies to evaluate the similarities and differences between isogenic human iPSCs and SCNT-ESC derivatives. We provide proof-of-concept that differentiated cells derived from human iPSCs are comparable to nuclear transfer-derived ESC counterparts with regard to transcriptional, epigenetic, physiological, and pharmacological features, given that they are genetically identical. We conclude that human iPSCs are capable of replacing SCNT for generating differentiated cells for drug testing and disease modeling.