Embryonic stem (ES) cells are pluripotent cells directly derived from early stage embryos that retain the ability to differentiate into all cell types. This unique feature is the basis of various applications of ES cell technology such as in vitro models of mammalian development, germline transgenesis to make knockout mice, and a generic source for cell therapy in regenerative medicine. To achieve success in these applications, the pluripotency of ES cells has to be kept stable during long-term culture in vitro, leading to the necessity of determining the molecular basis for maintaining ES self-renewal. This paper summarizes the recent progress in this area, focusing mainly on the LIF signaling pathway and the transcription factor Oct-3/4. Although it is still unclear how these components works together, a model is presented here that provides a plan to solve this problem.