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Penetrating self-inflicted injury is a mechanism that occurs with significant frequency at many trauma centers in the United States and internationally. With high rates of unemployment and growing numbers of individuals with mental illness, we expect more and more patients to present with these injuries. Additionally, there are known to be misconceptions about the seriousness of injuries that can occur when penetrating trauma is self-inflicted, especially with stab wounds. There is also often uncertainty among surgeons regarding how to treat these patients effectively in a multidisciplinary fashion while working with psychiatry services. Our goal was to review the epidemiology, mechanisms, anatomic considerations, role of substance use, and psychiatric illness in these injuries and the approach to evaluation and treatment of these patients.