The specification of germ cell fate in development initiates mechanisms essential for the perpetuation of genetic information across the generations. Recent studies in mice have shown that germ cell specification requires at least three key molecular/cellular events: repression of the somatic program, re-acquisition of potential pluripotency, and an ensuing genome-wide epigenetic reprogramming. Moreover, a signaling and transcriptional principle governing these processes has been identified, raising the possibility of inducing the germ cell fate precisely from pluripotent stem cells in culture. These advances will in turn serve as a basis to explore the mechanism of germ cell specification in other mammals, including humans. The recapitulation of germ cell development in humans in culture will provide unprecedented opportunities to understand the basis of the propagation of our genome, both under normal and diseased conditions.