Toxic shock syndrome (TSS) represents a fascinating example of immune activation caused by infection resulting in a dramatic and challenging clinical syndrome. TSS is commonly associated with tampon use and still causes significant morbidity and mortality in young healthy women. A misconception is that TSS presents with a skin rash and only occurs in women and children; however, it can occur in males and can present without skin changes. TSS presents initially as a febrile illness and within a few hours can progress to severe hypotension and multiple organ failure (MOF). Staphylococcus aureus and group A beta haemolytic streptococcus (GABHS) can secrete toxins from a small or hidden focus of infection and hence blood culture and sensitivity (C+S) tests can be negative, thereby making diagnosing this condition challenging. Clindamycin is superior to penicillin in the treatment of this condition and significantly decreases the mortality rate in TSS. However, there is also an important role for intravenous immunoglobulins (IVIG). Early intensive care unit (ICU) as well as surgical team involvement (in selected cases) is required to avoid mortality which may approach 70%.