Embryonic stem (ES) cells can replicate indefinitely while retaining the capacity to differentiate into functionally distinct cell types. ES cells proliferate and differentiate without detectable genetic changes, indicating that these processes are controlled by epigenetic factors. Here we describe what is known about the epigenetics of ES cells and speculate that a dynamic balance among at least three epigenetic elements (chromatin structure, DNA methylation, and microRNAs), in conjunction with transcription factors, contributes to the maintenance of pluripotence. Understanding the interactions among these factors will be critical to the development of improved strategies to reprogram differentiated cells or direct differentiation of pluripotent cells.