Human ES (hES) cells are pluripotent stem cells isolated from the inner cell mass (ICM) of blastocysts, with the theoretical capacity to differentiate in vitro to produce all somatic and germ cell types. The diverse differentiation repertoire of hES cells makes them ideal candidates for the generation of tissues for transplantation therapies and drug discovery. However, to realize the full potential of hES cells it will be necessary to characterize the mechanisms that control self-renewal and differentiation into specific cell types. We review here the recent developments to differentiate human ES cell into lineages including neural and cardiac. Further, by reference to the self-renewal system established in murine ES we will discuss the possible mechanisms of self-renewal in hES cells.