Streptococcus pyogenes (group A streptococcus, GAS) is a ubiquitous and important human bacterial pathogen. This organism possesses several virulence factors to establish infection. One of these, the streptococcal pyrogenic exotoxin B (SpeB), is the predominant secreted cysteine protease of GAS. SpeB cleaves or degrades host serum proteins such as human extracellular matrix, immunoglobulins, complement components, and even GAS surface and secreted proteins. Destruction of both host and bacterial proteins makes SpeB the key virulence factor in GAS pathogenesis. Although several lines of evidence have shown that SpeB is an important virulence factor of GAS, its role in streptococcal infection remains controversial. Here, we review several publications and describe our current understanding of SpeB in GAS pathogenesis.