Group A streptococci (GAS) express soluble and surface-bound virulence factors. Secreted streptokinase (SK) allelic variants exhibit varying abilities to activate host plasminogen (Pg), and GAS pathogenicity is associated with Pg activation and localization of the resulting plasmin (Pm) on the bacterial surface to promote dissemination. The various mechanisms by which GAS usurp the host proteolytic system are discussed, including the molecular sexuality mechanism of conformational activation of the Pg zymogen (Pg*) and subsequent proteolytic activation of substrate Pg by the S•KPg* and SK•Pm catalytic complexes. Substantial progress has been made to delineate both processes in a unified mechanism. Pm coats the bacteria by direct and indirect binding pathways involving plasminogen-binding group A streptococcal M-like (PAM) protein and host fibrin(ogen). Transgenic mouse models using human Pg are being optimized to mimic infections by SK variants in humans and to define in vivo combined mechanisms of these variants and PAM.