Human pluripotent stem cells (hPSCs) encompassing human embryonic stem cells and human induced pluripotent stem cells (hiPSCs) have a wide appeal for numerous basic biology studies and for therapeutic applications because of their potential to give rise to almost any cell type in the human body and immense ability to self-renew. Much attention in the stem cell field is focused toward the study of gene-based anomalies relating to the causative affects of human disease and their correction with the potential for patient-specific therapies using gene corrected hiPSCs. Therefore, the genetic manipulation of stem cells is clearly important for the development of future medicine. Although successful targeted genetic engineering in hPSCs has been reported, these cases are surprisingly few because of inherent technical limitations with the methods used. The development of more robust and efficient means by which to achieve specific genomic modifications in hPSCs has far reaching implications for stem cell research and its applications. Recent proof-of-principle reports have shown that genetic alterations with minimal toxicity are now possible through the use of zinc finger nucleases (ZFNs) and the inherent DNA repair mechanisms within the cell. In light of recent comprehensive reviews that highlight the applications, methodologies, and prospects of ZFNs, this article focuses on the application of ZFNs to stem cell biology, discussing the published work to date, potential problems, and future uses for this technology both experimentally and therapeutically.