This chapter provides an in-depth overview of substance use disorder (SUD) treatment in the street medicine context, emphasizing harm reduction, patient autonomy, and practical strategies for working with unsheltered populations. The chapter discusses commonly used substances—such as alcohol, opioids, methamphetamine, cocaine, and synthetic drugs—and outlines both their effects and associated risks. It highlights the complexity of polysubstance use and the variability in drug availability, contamination, and legal context across different regions. Drawing on interviews with experienced street medicine clinicians in the U.S. and Canada, the chapter presents real-world insights into low-barrier treatment approaches, including flexible medication-assisted treatment, withdrawal management, and psychosocial interventions. Special attention is given to the limitations of traditional care models and the ethical considerations of working with vulnerable populations. The chapter underscores the importance of reducing harm, working toward patient goals, and creatively adapting treatments to unpredictable environments. It also introduces practical tools such as the PAWSS screening tool for alcohol withdrawal and protocols for outpatient detox. This chapter equips street medicine providers with actionable, evidence-informed strategies to deliver compassionate, effective care to people who use drugs while living unsheltered.