Introduction  Despite its in vitro efficacy, penicillin often fails to eradicate Group A β-hemolytic streptococci (GABHS) from patients with acute and relapsing pharyngo-tonsillitis (PT). Objective  This review of the literature details the causes of penicillin failure to eradicate GABHS PT and the therapeutic modalities to reduce and overcome antimicrobial failure. Data Synthesis  The causes of penicillin failure in eradicating GABHS PT include the presence of β lactamase producing bacteria (BLPB) that "protect" GABHS from any penicillin; the absence of bacteria that interfere with the growth of GABHS; co-aggregation between GABHS and Moraxella catarrhalis; and the poor penetration of penicillin into the tonsillar tissues and the tonsillo-pharyngeal cells, which allows intracellular GABHS and Staphylococcus aureus to survive. The inadequate intracellular penetration of penicillin can allow intracellular GABHS and S. aureus to persist. In the treatment of acute tonsillitis, the use of cephalosporin can overcome these interactions by eradicating aerobic BLPB (including M. catarrhalis), while preserving the potentially interfering organisms and eliminating GABHS. Conclusion  In treatment of recurrent and chronic PT, the administration of clindamycin, or amoxicillin-clavulanic acid, can eradicate both aerobic and anaerobic BLPB, as well as GABHS. The superior intracellular penetration of cephalosporin and clindamycin also enhances their efficacy against intracellular GABHS and S. aureus.