Several lines of epidemiological and microbiological studies point to the multiple and critical roles of the nasopharynx of children-particularly those of pre-school age and attending day-care centres (DCCs)-in the emergence and spread of drug-resistant Streptococcus pneumoniae (DRP). A systematic yearly surveillance of the nasopharyngeal flora of children attending DCCs has been carried out in Lisbon since 1996. Molecular typing of several hundred DRP isolates showed that the great majority of DRP were represented by a relatively few clonal types that were frequently carried by many children in geographically distant DCCs and over several years of surveillance. The same epidemic DRP clones were also frequent among pneumococci causing both paediatric and adult disease worldwide. Penicillin-resistant pneumococci carry sequences of heterologous origin in their pbp genes and also in the recently identified murM: a gene essential for expression of penicillin resistance and for the unique cell wall structure of penicillin-resistant pneumococci. Virtually all DRP express only a limited number (five or six) of the very large genetic repertoire (up to 90) of serotypes available for this bacterial species and the serotypes of drug-resistant strains happens to be the same as the serotypes of drug-susceptible pneumococci that most frequently colonize pre-school age children. These observations strongly suggest that the nasopharynx of children is an important global ecological reservoir of DRP and may also play a critical role as the favoured anatomical site for the evolution of DRP.