Toxic shock syndrome (TSS) is a serious disorder with a worldwide prevalence of approximately 3/100,000 persons. TSS is mainly caused by Streptococcus pyogenes or Staphylococcus aureus. Thus, beta-lactam and lincosamides, such as clindamycin, are the first-line drugs. Yet, the mortality rate remains unacceptably high; highlighting the role of bacterial toxin-mediated activation of the inflammatory cascade in TSS pathogenesis. Further strategies should be targeted towards interfering with the interaction between bacterial toxins and host T cells. This paper aims to provide an overview of the epidemiology, pathomechanisms, and clinical presentation of TSS, and criteria for selecting drugs among available antibiotics.