In recent years, high-throughput technologies for investigating different aspects of sperm epigenome are gaining ground in order to elucidate the complex role of epigenetic regulation in sperm maturation, fertilization, and embryogenesis. From the point of view of transgenerational inheritance, the analysis of sperm epigenome could provide data related to abnormal epigenetic inheritance through the male germline, clarifying the possible effects on offspring health. Overall, these aspects could step into a leading role the sperm epigenome in the field of human reproduction. In this view, it is important to identify the better tools that should be considered for the profiling and analysis of sperm epigenetic markers. This chapter provides an overview on the current knowledge related to the technological aspects of the study of sperm epigenome focusing their strengths and weaknesses, as well as their clinical applications. In addition, we highlight the future challenges and opportunities as well as the questions that remain unanswered related to the structure and function of sperm.