Antibacterial resistance in pneumococci is increasing worldwide, primarily against beta-lactams and macrolides. Understanding the role played by molecular determinants of resistance, transformation and competence in the evolution of Streptococcus pneumoniae is important in addressing this trend. Data from the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) study indicate that about 40% of pneumococci display multidrug-resistant phenotypes (resistance to three or more antibiotics), with highly variable prevalence rates observed in different countries. Alterations in the structure of six penicillin-binding proteins (PBPs) have been described in S. pneumoniae (1a, 1b, 2x, 2a, 2b and 3), enabling resistance to beta-lactam antibiotics. Mechanisms conferring macrolide resistance include resistance mediated through the erm(B) gene, which results in macrolide-lincosamide-streptogramin B resistance, or through the mef(A) gene, which encodes an antibiotic efflux pump. Another variant, mef(E), is also expressed in S. pneumoniae; both mef(A) and mef(E) variants are associated with strains belonging to serotype 14. In addition to the selection pressure resulting from misuse of antibiotics, widespread vaccination programmes may contribute to changing pneumococcal epidemiology. Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7), the rate of invasive pneumococcal disease due to PCV7 serotypes has declined significantly in many countries, but some countries have reported an increase in non-PCV7 serotypes. This phenomenon, termed 'replacement', is associated with certain pneumococcal serotypes or clones (e.g. serotype 19A). Whether novel 'vaccine escape recombinant' pneumococcal strains are emerging or changes in distribution are part of a secular cycle remains to be determined.