Group A Streptococcus pyogenes pathogenesis involves multiple virulence mechanisms: M protein provides antiphagocytic properties and mediates molecular mimicry with cardiac myosin and sarcolemmal proteins; streptolysins O and S cause tissue destruction and hemolysis; hyaluronidase breaks down connective tissue facilitating bacterial spread; streptokinase converts plasminogen to plasmin dissolving fibrin barriers. Post-infectious immune complications arise from molecular mimicry: anti-streptococcal antibodies cross-react with cardiac tissue (myosin, laminin, valvular glycoproteins) causing rheumatic carditis, with synovial tissue causing migratory polyarthritis, and with basal ganglia neurons causing Sydenham chorea. Post-streptococcal glomerulonephritis involves immune complex deposition in glomerular basement membrane causing complement activation, neutrophil infiltration, and inflammatory glomerular damage presenting with hematuria, proteinuria, edema, and hypertension. The clinician must apply clinical decision rules, order appropriate diagnostics, prescribe targeted therapy, manage complications, and determine referral needs.