Plzf is a transcriptional repressor essential for maintaining spermatogonial stem cells in the testis. This study shows that Zfp145, which encodes Plzf, is crucial for spermatogenesis. Zfp145 is expressed in gonocytes and undifferentiated spermatogonia but absent in W/W mutants lacking these cells. Mice lacking Zfp145 experience progressive loss of spermatogonia with age, associated with increased apoptosis and loss of tubule structure, but without differentiation defects or loss of Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice showed altered gene expression profiles related to spermatogenesis. These results identify Plzf as a spermatogonia-specific transcription factor required for self-renewal and maintenance of the stem cell pool. Plzf is dynamically expressed during embryogenesis and plays a role in limb and axial skeletal patterning. It also exerts growth-suppressive activities by accumulating cells in the G0/G1 phase of the cell cycle. Spermatogenesis is a highly organized cyclic process involving mitosis, meiosis, and spermiogenesis. Spermatogonia, the mitotic germ cells in the adult testis, originate from primordial germ cells during embryogenesis. Plzf is expressed in the male gonad during embryogenesis and postnatal life, localized to gonocytes and spermatogonia. Plzf expression is restricted to spermatogonia, as shown by the absence of Plzf staining in W/W mutants lacking these cells. Zfp145-null mice have smaller testes and show degenerated tubules with absence of gametes at the basal membrane. This progressive loss of spermatogonia impairs spermatogenesis and reduces production of mature spermatozoa. Testes of Zfp145-null mice contain tubules with multilayered seminiferous epithelia, including some with mature spermatids, indicating that germ cells can initiate and complete the entire spermatogenic process. However, the number and sperm counts of Zfp145-null mice are much lower than those of littermate controls. The low numbers of mature sperm produced by Zfp145-null mice are not functional, as viable, actively motile sperm are too low for successful in vitro fertilization. Zfp145-null mice show progressive loss of spermatogonia and increased apoptosis, with no obvious tubule degeneration until 2 weeks of age. This suggests that the proliferative capacity of spermatogonia was already compromised at this early age. The loss of Zfp145 leads to depletion of the germline stem cells in testis. Microarray analysis of spermatogonia from Zfp145-null mice before testis degPlzf is a transcriptional repressor essential for maintaining spermatogonial stem cells in the testis. This study shows that Zfp145, which encodes Plzf, is crucial for spermatogenesis. Zfp145 is expressed in gonocytes and undifferentiated spermatogonia but absent in W/W mutants lacking these cells. Mice lacking Zfp145 experience progressive loss of spermatogonia with age, associated with increased apoptosis and loss of tubule structure, but without differentiation defects or loss of Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice showed altered gene expression profiles related to spermatogenesis. These results identify Plzf as a spermatogonia-specific transcription factor required for self-renewal and maintenance of the stem cell pool. Plzf is dynamically expressed during embryogenesis and plays a role in limb and axial skeletal patterning. It also exerts growth-suppressive activities by accumulating cells in the G0/G1 phase of the cell cycle. Spermatogenesis is a highly organized cyclic process involving mitosis, meiosis, and spermiogenesis. Spermatogonia, the mitotic germ cells in the adult testis, originate from primordial germ cells during embryogenesis. Plzf is expressed in the male gonad during embryogenesis and postnatal life, localized to gonocytes and spermatogonia. Plzf expression is restricted to spermatogonia, as shown by the absence of Plzf staining in W/W mutants lacking these cells. Zfp145-null mice have smaller testes and show degenerated tubules with absence of gametes at the basal membrane. This progressive loss of spermatogonia impairs spermatogenesis and reduces production of mature spermatozoa. Testes of Zfp145-null mice contain tubules with multilayered seminiferous epithelia, including some with mature spermatids, indicating that germ cells can initiate and complete the entire spermatogenic process. However, the number and sperm counts of Zfp145-null mice are much lower than those of littermate controls. The low numbers of mature sperm produced by Zfp145-null mice are not functional, as viable, actively motile sperm are too low for successful in vitro fertilization. Zfp145-null mice show progressive loss of spermatogonia and increased apoptosis, with no obvious tubule degeneration until 2 weeks of age. This suggests that the proliferative capacity of spermatogonia was already compromised at this early age. The loss of Zfp145 leads to depletion of the germline stem cells in testis. Microarray analysis of spermatogonia from Zfp145-null mice before testis deg