Specification of the germ cell lineage is fundamental in development and heredity. In mice, and presumably in all mammals, germ cell fate is not an inherited trait from the egg, but is induced in pluripotent epiblast cells by signaling molecules. Recent studies are beginning to uncover the signaling requirements and key transcriptional regulators for the specification of the germ cell lineage in mice, as well as the distinct properties that the specified germ cells acquire uniquely. Accordingly, the evidence suggests that germ cell specification is an integration of the repression of the somatic program, re-acquisition of potential pluripotency, and ensuing genome-wide epigenetic reprogramming. The accumulated knowledge will be critical for the reconstitution of this key lineage in vitro, which may provide a useful foundation for reproductive and regenerative medicine.