Male germ cells possess a unique epigenetic program and express a male-specific transcription profile. However, when its chromatin is passed onto the zygote, it expresses an transcription/epigenetic program characteristic of the zygote. The mechanism underlying this reprogramming process is not understood at present. In this study, we show that an extensive range of chromatin factors (CFs), including essential transcription factors and regulators, remodeling factors, histone deacetylases, heterochromatin-binding proteins, and topoisomerases, were removed from chromatin during spermiogenesis. This process will erase the paternal epigenetic program to generate a relatively naive chromatin, which is likely to be essential for installation of the zygotic developmental program after fertilization. We have also showed that transcription termination in male germ cells was temporally correlated with CF dissociation. A genome-wide CF dissociation will inevitably disassemble the transcription apparatus and regulatory mechanism and lead to transcription silence. Based on data presented in this and previous studies (Sun et al., Cell Research  17:117–134), we propose that paternal-zygotic transcription reprogramming begins with a genome-wide CF dissociation to erase the existing transcription program in later stages of spermatogenesis. This will be followed by assembling of the zygotic equivalent after fertilization. The transcription/epigenetic program of the male germ cell is transformed into a zygotic one using an erase-and-rebuild strategy similar to that used in the maternal-zygotic transition. It is also noted that transcription is terminated long after meiosis is completed and before chromatin becomes highly condensed during spermatogenesis. The temporal order of these events suggests that transcription silence does not have to be coupled to meiosis or chromatin condensation. Developmental Dynamics 237:1463-1476, 2008. © 2008 Wiley-Liss, Inc.