The process of spermatogenesis is a unique form of cellular differentiation and is regulated by genetic and epigenetic factors. Recent studies have shown that some epigenetic factors (histone variants and histone modifying enzymes) are exclusively expressed during spermatogenesis; the disruption of these factors leads to spermatogenic defects. Also, during spermatogenesis a key epigenetic process termed meiotic sex chromosomes inactivation (MSCI) occurs; MSCI leads to the inactivation of most genes on the X and Y chromosomes; however, the mechanism of MSCI is distinct from X inactivation in female somatic cells. Furthermore, a new class of non-coding RNAs (i.e., piRNAs) has recently been identified which is exclusively expressed during spermatogenesis. This review discusses recent advances in our understanding of epigenetic mechanisms that operate during spermatogenesis with specific emphasis on histone modifications, MSCI and non-coding RNAs. Finally, we propose that spermatogenesis can be a powerful experimental system to dissect epigenetic mechanisms of gene regulation.