When environmental conditions compromise survival, single celled organisms, such as the budding yeast S. cerevisiae, induce and complete a differentiation program called sporulation. The first step consists of meiosis, which generates genetic diversity within the eventual haploid cells. The post-meiotic maturation stage reinforces protective barriers, such as the spore wall, against deleterious external conditions. In later stages of sporulation, the spore nucleus becomes highly compacted, likely sharing certain characteristics with the metazoan male gamete, the spermatozoon. The sporulation differentiation program involves many chromatin-related events, including execution of a precise transcription program involving more than one thousand genes. Here, we review how chromatin structure and genome reprogramming regulate the sporulation transcription program, and how post-meiotic events reorganize spore chromatin.