Protamines are the most abundant nuclear proteins packaging the mammalian male genome in the sperm nucleus. The main proposed functions of these proteins are condensation and streamlining of the sperm cell, protection of the genetic message, and contribution to the epigenetic organisation of the paternal genome. Different studies have demonstrated the presence of an altered expression of protamines in some infertile patients and a link to decreased DNA integrity. However, in addition to protamines, about 5–15% of the male sperm genome is also complexed with histones and histone variants. Furthermore, present proteomic approaches based on mass spectrometry are also identifying additional chromatin-associated proteins. Of importance, it has been demonstrated that there is a differential distribution of genes into the histone- and protamine-associated regions of the sperm nucleus, which supports the idea of an epigenetic marking of the sperm nucleoprotein, with potential relevance in early embryonic development.