Pneumococcus is a major cause of community-acquired infections and the most common cause of death due to CAP. Today, efficacy of empiric treatment is doubtful because of the rapid escalation of pneumococcus resistance to â-lactams and macrolides, as well as, of its multi-drug resistance, that is, the additional resistance to various other common agents. Therefore, microbiologists must work according to international recommendations, in order to provide accurate information about pneumococcus resistance, while clinicians must be alert, adopting laboratory results in order to avoid treatment failures. The incidence of resistance to â-lactams and macrolides is highly variable among countries. Specifically, penicillin resistance is higher in SW and NE Europe, as well as in S. Africa, while erythromycin resistance has escalated dramatically, especially in the countries of NE Asia. Finally, pneumococcus multi-resistance, higher among pneumococcal strains displaying penicillin resistance, provides new limitations in antibiotic treatment efficacy. Geographical variations and risks for treatment failure address the need for clinical trials at national level and in all countries in order for useful empiric schemes to be developed. Pneumon 2005, 18(3):265-276.