Deep sternal wound infection (DSWI), also known as mediastinitis, is a serious and potentially fatal condition. The diagnosis and treatment of DSWI are challenging. In this current narrative review, the epidemiology, risk factors, diagnosis, and surgical and antimicrobial management of DSWI are discussed. Ideally, the management of DSWI requires early and sufficient surgical debridement and appropriate antibiotic therapy. When foreign material is present, biofilm-active antibiotic therapy is also needed. Because DSWI is often complex, the management requires the involvement of a multidisciplinary team consisting of cardiothoracic surgeons, plastic surgeons, intensivists, infectious disease specialists, and clinical microbiologists.