Defining the molecular mechanisms maintaining stemness - self-renewal and pluripotency - of Embryonic stem (ES) cells, as well as induced pluripotent stem (iPS) cells is of great interest for understanding early development and for their potential therapeutic applications in regenerative medicine. Systematic understanding of the mechanisms controlling the stemness of pluripotent stem cells relies on high-throughput tools to define gene expression and regulatory networks at the genome level. Systems biology approaches have revealed highly interconnected ES cell specific regulatory networks in which multiple cis and trans regulatory elements are involved. Interestingly, recent studies have suggested that pluripotent stem cells and cancer cells share common features, notably self-renewal and a block in differentiation.