Hormone Therapy (HT) remains the standard pharmaceutical treatment for managing menopausal symptoms. However, since the Women’s Health Initiative’s negative report on HT in 2002, many women seek alternatives such as botanical dietary supplements (BDS). Black cohosh is one of the leading BDS that women take for menopause and it was also traditionally used by American Indians. Although black cohosh was extensively studied, there are still numerous botanicals historically used by American Indians that lack scientific investigations on safety, efficacy, and support for traditional use. In collaboration with the UIC/NIH Center for Botanical Dietary Supplements Research and the Chicago Botanic Garden (CBG), 15 plants were selected from 164 native plant species to evaluate potential benefits for women’s health. This project seeks to identify (anti)estrogenic, chemopreventive, and anti-inflammatory activity of the studied plants, isolate the active compounds from the most active plants through bioassay-guided fractionation, and support traditional American Indian knowledge.