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Objectives. To understand the barriers and facilitators that lactation professionals and supporters (LPSs) in the Appalachian region of the United States experience when providing services and support to families. Methods. We used a mixed-methods explanatory sequential design with a survey of LPSs in Appalachia (March‒July 2019), followed by semistructured interviews with LPSs (January‒April 2020). We summarized survey responses descriptively and analyzed interview transcripts thematically. Results. The survey was completed by 89 LPSs in Appalachia. We conducted semistructured interviews with 20 LPSs. Survey participants most commonly identified challenges with other health care providers, hospital practices, and non‒medically indicated supplementation as barriers. Interview participants described challenges with clients' families not supporting breastfeeding, difficulty reaching clients, limited numbers of LPSs, and lack of racial/ethnic diversity among LPSs. LPSs identified the need for training in lactation and substance use, mental health, and birth trauma, and supporting lesbian, gay, bisexual, transgender, queer or questioning, plus (LGBTQ+) families. LPSs described social media and telehealth as both facilitators and barriers. Social support from other LPSs was a facilitator. Conclusions. LPSs in Appalachia face various challenges. Addressing these challenges has the potential to improve the lactation support and services families in Appalachia receive. ( Am J Public Health . 2022;112(S8):S797-S806. https://doi.org/10.2105/AJPH.2022.307025).