Recurrent and persistent acute otitis media (AOM) is a common problem, affecting close to 20% of children in their first years of life. It presents a therapeutic challenge to physicians, particularly as beta-lactamase-producing Haemophilus influenzae, as well as penicillin- and, more recently, macrolide-resistant Streptococcus pneumoniae are often responsible for AOM in these patients. Intramuscular ceftriaxone (50 mg/kg, once daily for 3 days) has been shown to be effective in treating nonresponsive AOM, but there have been relatively few clinical trials exploring oral antibiotic regimens. Higher doses of commonly used antibiotics (amoxicillin-clavulanate ratio, 14:1 ratio and azithromycin 60 mg/kg divided into three equal once daily doses) have demonstrated high rates of clinical success. These studies will be discussed together with a review of the clinical and microbiologic characteristics of this disease. We will also address the impact that the pneumococcal conjugate vaccine may have on the microbiology of recurrent and persistent AOM.