The incidence of severe group A streptococcal infection and the streptococcal toxic shock syndrome has increased since 1986. In contrast to earlier times, aggressive streptococal infection is now more likely to affect patients between 20 and 50 years of age who do not have predisposing underlying diseases. Its viral-like prodrome can often mislead clinicians and patients, and nonsteroidal anti-inflammatory drugs can mask symptons. Prompt antibiotic therapy is mandatory, but even with aggressive treatment mortality may be 30-50%. Though penicillin is the drug of choice for most streptococcal infections, its efficacy is poor in deep-seated soft-tissue infections, and is in part related to the in vivo inoculum effect and 'the physiologic state of the organism'. This paper reviews the molecular mechanisms responsible for these phenomena and demonstrates the greater efficacy of clindamycin in an experimental model of severe streptococcal infection.