Specialized cells can be reverted back to induced pluripotent stem cells (iPSCs), and this “reprogramming” holds enormous promise for drug discovery as well as cell transplantation approaches towards the treatment of degenerative diseases. Our goal is to understand the genes and pathways that regulate the process of generation of human iPSCs. During the second year of this award we have made major progress toward this goal. We have discovered several novel cellular pathways that operate in specialized cells and act to oppose the process of reprogramming. We have characterized some of these key pathways in detail, including their timing of action, how they affect the reprogramming process, and how they interact with one another. These results keep us fully on track towards the goal of achieving a deeper understanding of the process of reprogramming human cells to the pluripotent stem cell state.