Dr. James Todd first described toxic shock syndrome (TSS) in 1978. His case series report included seven children and adolescents who presented with a high fever, headache, confusion, conjunctival hyperemia, a scarlatiniform rash, subcutaneous edema, vomiting, watery diarrhea, and oliguria leading to severe, prolonged shock. Consistent laboratory findings included evidence of acute renal failure, liver injury, and dysfunction and disseminated intravascular coagulation. One patient died, one developed gangrene of the toes, and all six survivors developed desquamation of the skin on their hands and feet during convalescence. Staphylococcus aureus (S. aureus) was isolated from mucosal (nasopharyngeal, vaginal, tracheal) or sequestered (empyema, abscess) sites but not from blood. These isolates produced an exotoxin, which caused a positive Nikolsky sign when inoculated into a newborn mouse. In the years that followed, the reported association of TSS with high-absorbency tampon use garnered substantial media attention and delivered an important public health message, albeit with more hyperbole than necessary. During that era, statements from Dr. Todd about “the myths, partial truths, and gross misconceptions promulgated in the media” sought to bring better education and additional perspective to the problem. Years later, the term “superantigen” was coined to describe a stimulus that causes a substantial expansion and proliferation of T lymphocytes leading to massive production and release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1, IL-2, and IL-6. The inflammatory response is responsible for the clinical signs and symptoms seen in the patient with TSS. The end result of this intense cascade of events is life-threatening cardiovascular collapse. TSS is thus mediated by a complex interaction of superantigens with the host that results in extensive immune dysregulation and multi-organ dysfunction. Infections caused by Gram-positive organisms that produce superantigens, such as toxic shock syndrome toxin-1 (TSST-1) and enterotoxins SEB and SEC, produced by some strains of S. aureus, and streptococcal pyrogenic exotoxin A (SPE-A), produced by some strains of Streptococcus pyogenes, can lead to TSS. Clinically, TSS is an acute systemic illness, characterized by fever, hypotension, and involvement of at least two or more organ systems. Established case definitions exist for TSS caused by strains of S. aureus and S. pyogenes with some important differences between the two.