Since human embryonic stem cells (hESCs) were first derived from preimplantation blastocysts, the advent of hESC-based therapy for a wide range of cellular degenerative diseases has been greatly anticipated. However, standard methods for hESC derivation result in embryo destruction and have been under intense ethical debate. Various alternative approaches have been devised since then generate pluripotent stem cells (PSCs) without embryo destruction. These new advances in stem cell derivation include the derivation of human-induced PSCs by introducing genetically-defined factors into adult somatic cells, the generation of hESCs from single blastomeres, and the generation of non-human primate ESCs through somatic cell nuclear transfer (SCNT). They have overcome the major problems inherent in conventional hESCs. With these advances in the derivation of new PSC types, it is essential to carefully examine the nature of the pluripotency expressed by these cells and the mechanism regulating the reprogramming process through large scale genetic and epigenetic screening. We reviewed these new methods of hPSC derivation and addressed some of the problems associated with these advances. A brief summary of new advances in genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) technology and their implications for stem cell research were provided and discussed.