Streptococcal pyrogenic exotoxin B (SpeB) is a protease secreted by group A streptococci and known to degrade a wide range of host and GAS proteins in vitro. Although the role of SpeB in GAS infection is debated, recent evidence has conclusively demonstrated that SpeB is critical for the pathogenesis of severe invasive disease caused by GAS. Genetic inactivation of the speB gene results in significantly decreased virulence in a necrotizing fasciitis model of infection. Production of fully active SpeB by GAS is extremely complex. Following transcription and translation the SpeB protein is secreted as an inactive zymogen, which is autocatalytically processed through a series of intermediates to form an active protease. Each step from transcription to protease activation is tightly controlled and regulated by the bacterial cell reflecting the critical role played by this virulence factor in GAS infection. Here we review the molecular aspects of SpeB production by GAS from transcription to activation and the multiple layers of control involved.