Infections with Clostridium perfringens usually manifest locally or spread to sepsis with multiorgan involvement, hemolysis or septic shock. Central nervous system (CNS) manifestations are rare and most frequently comprise meningitis with or without pneumencephalon, encephalitis, plexitis, cerebral abscess, or subdural empyema. The course of CNS affections is usually foudroyant and the outcome fatal. Neuromuscular manifestations of C. perfringens infections are much more frequent than CNS manifestations and comprise myonecrosis (gas gangrene), rhabdomyolysis, myositis, fasciitis, affection of the neuromuscular transmission, or affection of the peripheral nerves. C. perfringens infections usually start from the site of a recent surgical wound or trauma, a gastrointestinal or urogenital problem, or occur in association with malignancy. In quite a number of cases the source of origin remains speculative. Treatment of choice is surgical debridement of the infectious focus with radical removal of all necrotic tissue, resection of the corresponding lymphatics in addition to antibiotic therapy with penicillin G, aminoglycosides, or clindamycin or hyperbaric oxygenation. Despite these therapeutic options, the prognosis of CNS and neuromuscular involvement in an infection with C. perfringens is still poor. Only focal infections or clostridial brain abscesses may eventually have a more favorable outcome, if surgery and antibiotics are instantly provided. Generally, early recognition of the infectious agent is of paramount importance to prevent from spreading and the development of severe hemolysis, septic shock, or death.