Stem cell therapies show great potential for use in regenerative medicine, though advancements in safe stem cell technology need to be realized. Human induced pluripotent stem cells (hiPSCs) hold an advantage over other stem cell types for use in cell-based therapies due to their potential as an unlimited source of rejuvenated and immunocompatible SCs which do not elicit the ethical and moral debates associated with the destruction of human embryos. Towards realization of this potential this review focuses on the recent progress in DNA-and xeno-free reprogramming methods, particularly small molecule methods, as well as addresses some of the latest insights on donor cell gene expression, telomere dynamics, and epigenetic aberrations that are a potential barrier to successful widespread clinical applications.