Many basic, mechanistic studies of how sex steroids alter vascular function proceeded from Dr. Bush's seminal epidemiologic observations that noncontraceptive use of estrogen reduced all-cause and cardiovascular mortality. However, translating findings from these basic science studies into clinical trials and clinical guidelines has been controversial. This commentary reviews the development of sex steroid vascular research, identifies mechanisms by which sex steroids affect vascular function, reviews findings from recent clinical hormone trials, and identifies challenges and the need for continued funding of such investigations.