To fulfill the promise of pluripotent stem cells, both embryonic and induced pluripotent stem cells, it is essential to fully understand their properties and how those properties can be manipulated to make any cell in the human body. The best way to reach that goal is to understand the relationships between these cells that grow in a culture dish in the laboratory and the equivalent cells in the developing embryo. As working with human embryos comes with many ethical concerns, an important alternative is the mouse model. Indeed, much of what we have learned in the mouse model has later been confirmed in human. Therefore, we use a combination of the mouse model and human cells to dissect the molecular basis of stem cell function and differentiation toward adult tissues. In particular, we have been focusing on a class of molecules called small RNAs that were only discovered in the 1990s and became widely appreciated in the past decade. There are several classes of these small RNAs, two of which our lab focuses on, microRNAs and endogenous siRNAs. We have found these small RNAs are essential for normal mammalian development and growth and differentiation of stem cells. In the past year, we have been looking more deeply into the mechanism by which the mammalian egg suppresses one of these classes of small RNAs, the microRNAs, but not the other, the endogenous siRNAs. We have also been studying how microRNAs are used shortly after fertilization first to maintain pluripotency (the ability to make all cells of the body) and then to promote differentiation into what eventually will become all the adult tissues. Understanding these mechanisms should enable us to adopt them in order to manipulate many cells to become other types of cells through a process called reprogramming. Reprogramming is the cornerstone of regenerative medicine as it allows one to replace damaged tissues. In other experiments, we have been looking into how microRNAs interact with additional molecular mechanisms in the cells. In particular, we have been studying the association of microRNAs and epigenetic changes in the cells. Understanding how these two mechanisms work together will enhance our ability to reprogram cells. Finally, we continue to tackle the role of the other class of small RNAs, the endogenous siRNAs. We are using reporters, genetic manipulation, and rescue strategies to discover the first examples of endogenous siRNA–gene interactions in mammals, once again focusing on early embryonic development. Together these results are giving new and important insights into the role of small RNAs in early embryonic development. This research is expected to enable to us to more easily manipulate cell fates to produce high quality cells that could be used to study diseases of many types as well as reintroduce healthy tissue into patients with degenerative diseases.