SummaryMulticellular animals are a diverse lot, with widely varied body plans and lifestyles. One feature they share, however, is a nearly universal reliance on sexual reproduction for species propagation. Humans have long been fascinated by human sex differences and formal theories on how human sex is determined date at least to Aristotle (in De Generatione Animalium, ca. 335 BCE). However, it is only in the past couple of decades that the genetic and molecular programs responsible for generating the two sexes have been understood in any detail. Sex, it turns out, can be established by many very different and fast-evolving mechanisms, but often these involve a conserved class of transcriptional regulators, the DM domain proteins.