Yellowroot (Xanthorhiza simplicissima Marshall, Ranunculaceae) is a low-growing deciduous shrub native to hardwood forests in the eastern United States. This review synthesizes existing knowledge about yellowroot’s natural and cultural history including traditional uses, contemporary applications, and future implications. Emphasis is placed on the southern Appalachian mountain region, which is the core of its cultural importance. Natural history and ethnobotanical knowledge about yellowroot were collected from published literature, oral histories, and field observations. While it was first described by botanists in the 18th Century, yellowroot was already a well-established and culturally significant plant to the Native peoples of southern Appalachia for centuries. At least 34 Indigenous medicinal and craft uses are documented, confirming that yellowroot was, and to an extent still is, a culturally significant plant for Indigenous people in the southern Appalachian region. European and African American settlers to the region also incorporated the plant into many of their folk traditions, and wild harvesting and cultivation continues to this day. Modern analytical techniques have identified key phytoactive compounds in yellowroot extracts, lending credence to its traditional medicinal uses and potential applications in modern medicine.