Dietary restriction (DR) remains the most reproducible and consistent laboratory intervention to extend lifespan and improve health in mammals. DR has been primarily characterized in males due to issues of cost, perceived heightened variability amongst females, and the misconception that the reproductive system is the only important difference between sexes in mammals. In reality, existing data point to clear sex differences in mammalian responses to DR. Here we discuss recent advances in our understanding of sex differences in the responses to DR in rodent models.