Purpose of Review <p>Skin and soft tissue infections are the primary cause of hospitalization in persons who inject drugs (PWID). This review aims to address pathogenesis and microbiology of these infections with discussion of how these infections present, how they can be diagnosed, and subsequently how they should be treated.</p> Recent Findings <p>A multidisciplinary approach to these episodes that includes adequate infectious disease, surgical, and addiction medicine care, and harm reduction counseling both in the inpatient and outpatient setting is paramount to ensuring treatment success and further patient engagement in the healthcare system.</p> Summary <p>SSTI in PWID can progress to severe disease and require significant healthcare utilization. A thorough evaluation including imaging, empiric antimicrobial therapy tailored to patient risk factors, and consideration of early transition to oral or long-acting therapies are important aspects of treatment success. Multidisciplinary care that includes addiction medicine with harm reduction counseling can lead to prevention of future infections.</p>