Skin and soft tissue infections (SSIs) are one of the many infectious diseases that can be treated by outpatient parenteral anti-infective therapy (OPAT). Determining whether a patient with SSIs is treated topically, orally, or parenterally depends on the severity of infection and host factors. The decision to hospitalize, initiate, or transition to OPAT with SSIs depends on the medical assessment and consideration of available resources for OPAT. Anti-infective selection depends on the clinical presentation, likely organisms, pharmacodynamics, pharmacokinetics, and drug stability.