Gametogenesis is a complex process that results in a highly differentiated gamete capable of transmitting genetic and epigenetic information to the next generation. In the cases of mammalian spermatogenesis and yeast sporulation, an extreme post-meiotic compaction of the genome is key to gamete function. While genome compaction in sperm is reliant upon a histone-to-protamine transition, yeast spores accomplish compaction with a full complement of histones. Although the mechanisms behind such striking chromatin dynamics are largely unknown, several histone variants and post-translational modifications, especially acetylation of histone H4, have been implicated in these processes. The following studies elucidate the roles of two proteins, BRD4 and the linker histone (Hho1), in chromatin compaction during mouse spermatogenesis and yeast sporulation, respectively. In the post-meiotic phase of mouse spermatogenesis, BRD4 forms a ring structure around the haploid nucleus at the cytoskeletal base of the developing acrosome, which has been implicated in nuclear compaction and shaping. Chromatin immunoprecipitation followed by mass spectrometry and sequencing in post-meiotic cells revealed that BRD4, a bromodomain-containing protein, binds to acetylated histone H4 and is enriched in intergenic regions of the genome where histone replacement by protamines is most predominant in mature sperm. Thus, BRD4 may provide a structural link between the contractile force of acrosome formation and the removal of acetylated histones from the genome. In contrast to sperm, spores must use a histone-based chromatin compaction mechanism. During sporulation, Hho1 plays a dual role: transcriptional repression and nuclear compaction. Hho1 is depleted during meiosis and enriched in post-meiotic spore chromatin. Moreover, Hho1 shows a high genome-wide binding correlation with Ume6, the master repressor of meiotic genes. Meiotic depletion of both of these proteins may lead to the activation of key sporulation genes. In addition, knockout of HHO1 revealed its necessity in meiotic progression and post-meiotic genome compaction. These data provide support to the interesting hypothesis that protamines are evolutionarily derived from linker histones: Hho1 may play the role of protamines in yeast. Taken together, these studies in mouse and yeast highlight the complexity of mechanisms developed in diverse eukaryotic systems to facilitate the compaction of the gamete genome.