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Primordial germ cells (PGCs) are the embryonic precursors of the adult gametes. Although restricted in developmental potency, PGCs express many of the same molecular markers as pluripotent embryonic stem (ES) cells and can give rise to embryonal carcinoma (EC) cells, the stem cells of testicular tumors, in vivo. Likewise, when exposed to specific growth factors in vitro PGCs can be converted into pluripotent embryonic germ (EG) cells. Here, we propose that genes differentially expressed between PGCs and ES cells are good candidates for regulating germline development. To identify genes important in regulating germ cell development and mammalian fertility, we performed suppression subtraction hybridization (SSH) between PGCs and ES cells whole gene set. Using this method, we identified the transcriptional coactivator/histone acetyltransferase CREB-binding protein (CBP) as being highly expressed in PGCs compared to ES cells. To elucidate the function of CBP in PGCs, we generated mice with a PGC-specific deletion of CBP. Loss of CBP in PGCs leads to increased apoptosis and subsequent reduction in PGC numbers. These data indicate an essential role for CBP in maintaining normal germ cell development.