© 2020 The development of organ fibrosis has garnered rising attention as multiple diseases of increasing and/or high prevalence appear to progress to the chronic stage. Such is the case for heart, kidney, liver, and lung where diseases such as diabetes, idiopathic/autoimmune disorders, and nonalcoholic liver disease appear to notably drive the development of fibrosis. Noteworthy is that the severity of these pathologies is characteristically compounded by aging. For these reasons, research groups and drug companies have identified fibrosis as a therapeutic target for which currently, there are essentially no effective options. Although a limited body of published studies are available, most literature indicates that in multiple organs, premenopausal women are protected from developing severe forms of fibrosis suggesting an important role for sex hormones in mitigating this process. Investigators have implemented relevant animal models of organ disease linked to fibrosis supporting in general, these observations. In vitro studies and transgenic animals models have also been used in an attempt to understand the role that sex hormones and related receptors play in the development of fibrosis. However, in the setting of chronic disease in some organs such as the heart older (postmenopausal) women within a few years can quickly approach men in disease severity and develop significant degrees of fibrosis. This review summarizes the current body of relevant literature and highlights the imperative need for a major focus to be placed on understanding the manner in which sex and the presence or absence of related hormones modulates cell phenotypes so as to allow for fibrosis to develop.