Fusion of sperm and egg generates a totipotent zygote that develops into a whole organism. Accordingly, the “immortal” germline transmits genetic and epigenetic information to subsequent generations with consequences for human health and disease. In mammals, primordial germ cells (PGCs) originate from peri-gastrulation embryos. While early human embryos are inaccessible for research, in vitro model systems using pluripotent stem cells have provided critical insights into human PGC specification, which differs from that in mice. This might stem from significant differences in early embryogenesis at the morphological and molecular levels, including pluripotency networks. Here, we discuss recent advances and experimental systems used to study mammalian germ cell development. We also highlight key aspects of germ cell disorders, as well as mitochondrial and potentially epigenetic inheritance in humans.