The history of Streptococcus pneumoniae diseases dramatically changed with the introduction into the immunization schedule of infants and children of the first pneumococcal conjugate vaccine, the one containing 7 (PCV7) of the most common pneumococcal serotypes (STs) causing invasive pneumococcal diseases (IPDs). Where PCV7 was largely used, incidence of both IPDs and non-invasive pneumococcal diseases (nIPDs) in vaccinated children and in unvaccinated subjects of any age, mainly the elderly, significantly decreased. Unfortunately, the impact of PCV7 administration was slightly lower than expected, as the reduction in infections due to vaccine serotypes (STs) was accompanied by a significant increase in the number of IPDs and nIPDs due to STs not included in the vaccine. To overcome this problem, two PCVs containing 10 (PCV10) and 13 (PCV13) STs, chosen among those emerging, were developed and licensed. However, ST replacement occurred again. Moreover, the new PCVs showed little effectiveness in the prevention of infection due to non-encapsulated STs and to ST3. Next-generation S. pneumoniae vaccines able to prevent pneumococcal infections regardless of infecting ST are urgently needed. For the moment, the use of available PCVs remains fundamental because their benefits far outweigh any concerns for emerging STs.