With the advent of increasing molecular characterization of individual differences it has become ever more important to understand how we might wisely individualize our approach to hormone use. The need to individualize in turn has spurred an interest in determining and understanding more about how estrogens differ. From the clinical point of view we know that not all women are the same and we know that not all estrogens are the same. But which of the differences between women or hormones are the ones that really matter when making clinical decisions about birth control or menopause management? When transdermal estradiol formulations for menopause management became available in the early 1990s the dogma that all estrogens were equivalent was called into question. It was recognized that the transdermal route of administration of estradiol had less hepatic impact than the oral route and that this might confer benefits including a reduced risk of venous thromboembolism. This line of reasoning seemed to make sense until a recent report (Cole et al. Obstet Gynecol 2007;109:339-346) showed that the transdermal contraceptive patch leads to higher rates of venous thromboembolism than oral contraceptives. Taken together these observations beg the question as to whether route of administration of estrogens does indeed matter. To dissect these findings we must consider the pharmacologic attributes of different estrogen preparations and the physiologic mechanisms that are influenced by type route of administration and dosage of estrogen formulations. The goal is to illustrate the concept that not estrogens are the same and to highlight our knowledge gaps. We will likely be afforded a more clinically relevant perspective about the clinical differences between estrogens that are more chemically similar as we learn more about how each differentially harnesses intracellular machinery such as protein chaperones.