Acute pharyngotonsillitis caused by beta-haemolytic group A streptococcus (GAS) is a common childhood disease. Phenoxymethyl penicillin remains the drug of choice, as no resistance has been reported so far. Nevertheless, the failure of penicillin to eradicate streptococci from the throat occurs in up to 35% of patients with pharyngotonsillitis, and might present clinical concern. Various explanations have been proposed over the years to account for this perplexing phenomenon. Among these are coexistence of oropharyngeal beta-lactamase-producing bacteria that degrade penicillin, growth interference by aerobic and anaerobic commensals, penicillin tolerance, reinfection, and poor antibiotic compliance. Although GAS has been considered an extracellular pathogen, recent studies have demonstrated that strains of this bacterium can internalize epithelial cells both in vitro and in vivo. The intracellular niche may protect the bacterium from penicillin that does not gain high intracellular concentration. In support of this hypothesis, GAS strains were shown to survive 4-7 days inside cultured epithelial cells. In addition, it was found that GAS strains isolated from patients with eradication failure harbour the internalization-associated gene, prtF1/sfbI, in higher prevalence than do strains recovered from patients with successful eradication. Thus, internalization and intracellular survival represent a novel explanation for penicillin eradication failure.