Purpose of Review <p>With the advent of direct-acting antiviral agents (DAA), reduction of hepatitis C infection (HCV) has become a public health priority. The World Health Organization’s goal of global elimination of HCV by 2030 has brought to light the challenges in treating certain populations. This review examines the burden of HCV infection on unhoused individuals and people who use substances in the United States in the last five years, and presents best practices in patient care and treatment.</p> Recent Findings <p>Findings highlight the burden of HCV on housing insecure persons and those who use substances. Engaging these populations in care remains challenging, especially due to the stigma associated with housing status, concurrent substance use, and the completion of treatment. Programs that couple treatment with existing services and provide a “one stop shop” have shown to increase treatment retention and completion.</p> Summary <p>Elimination of HCV is a global, and achievable, goal. Programs designed to treat HCV would benefit from focusing on engaging traditionally hard-to-reach populations of housing insecure persons and persons who use substances through proactive outreach, flexibility in delivery, and utilizing nontraditional medical settings and care models.</p>