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During the differentiation of haploid male germ cells, or spermiogenesis, the organization of the genome undergoes a profound and unique transformation, resulting in extreme genome compaction. This maturation involves a structural transition of the genome from a nucleosome-based structure to a nucleoprotamine-based structure, which is only present in spermatids and spermatozoa. Despite the paramount importance of this fundamental transformation of the genome organization during the generation of spermatozoa, we have remained in the dark about its molecular basis. Today, thanks to systematic approaches involving the discovery of new histones, their post-translational modifications and the associated factors, as well as large-scale structural and functional studies, we are able to propose the first molecular models explaining the genome-wide transformation of the nucleosome and the establishment of a compact, transportable, and functional male genome. This review summarizes the major advances made in recent years and our current understanding of the mechanisms driving this unique process in biology.