A major current molecular evolution challenge is to link comparative genomic patterns to species’ biology and ecology. Breeding systems are pivotal because they affect many population genetic processes, and thus genome evolution. We review theoretical predictions and empirical evidence about molecular evolutionary processes under three distinct breeding systems—outcrossing, selfing, and asexuality. Breeding systems may have a profound impact on genome evolution, including molecular evolutionary rates, base composition, genomic conflict, and possibly genome size. However, while asexual species essentially conform to theoretical predictions, the situation is less simple in selfing species. We discuss the possible reasons to potentially explain this paradox. In reverse, comparative and population genomic data and approaches help revisiting old questions on the long-term evolution of breeding systems.