De novo mutations (DNMs), i.e. genetic alterations not inherited from either parent, are an important contributor to disease, causing severe developmental disorders in ~1 in 300 births. Most DNMs (>80%) originate during spermatogenesis (sperm cell production) and their frequency increases with paternal age. We have previously described a mechanism taking place in the testis of all men that contributes to the paternal age-related increase in pathogenic DNMs called ‘selfish selection’ – whereby specific pathogenic DNMs arising in spermatogonial stem cells lead to their clonal expansion over time. This process explains the paternal age-effect and high birth prevalence observed for several inherited disorders that occur up to 1000-fold more frequently than background. Importantly, because the spermatogonial stem cells provide a source of heritable material, this phenomenon has long-term implications that extend far beyond the individual in whom it takes place, and is predicted to affect disease prevalence, apparent de novo mutation rate and the evolution of our species.