This article is a personal perspective on male infertility, a condition that is not only extremely prevalent but also a major reason for couples to resort to ART. The introduction of ICSI as a form of facilitated fertilization had a revolutionary impact on our capacity to treat cases of male infertility associated with severely compromised semen quality. However, the widespread use of this technique is also thought to pose risks in terms of the incidence of miscarriage, the health and wellbeing of the offspring and perpetuation of the infertile phenotype into future generations. Furthermore, the advent of ICSI curtailed intellectual interest in the underlying aetiology of male infertility or the development of non-invasive therapeutic strategies that target the male patient rather than the physical deployment of his gametes. As a consequence, progress on elucidating the pathological mechanisms responsible for male infertility has been extremely slow. Genetic and/or epigenetic defects are certainly involved in many cases and may involve mutations/splicing defects affecting the integrity of the testicular RNA profile, as well as the overall kinetics of the transcription process. In addition, spermatogenesis is disrupted by a variety of factors (age, smoking, obesity) many of which are thought to influence fertility and the integrity of sperm DNA through the creation of oxidative stress. Determining the relative contributions of oxidative stress and genetic/epigenetic mutations to the aetiology of male infertility will be a major focus for future research in this important but neglected area.