Germ cells are absolutely essential for fertility. Aberrant germ cell development can result in abnormal gonadal function, incomplete embryogenesis and infertility, or germ cell tumors. Our understanding of the molecular regulation of normal germ cell development in mammals has progressed significantly due to the utility of the mouse as a genetic model system. However, the molecular regulation of human germ cell development is almost completely unknown due to the historical lack of a malleable model. The purpose of this review is to compare the cell-based events leading up to the specification of the germ cell lineage in both mice and humans and to discuss some of the key signaling pathways that have recently been identified, which regulate germ cell specification. In addition, the new cell-based models for differentiating germ cells from both mouse and human embryonic stem cells (ESCs) will be summarized.