Serotype replacement in invasive pneumococcal disease threatens to undermine the most costly vaccination programme currently undertaken. However, the effects of replacement on public health have varied geographically. Striking differences have emerged between the UK and USA, countries that otherwise often resemble each other epidemiologically. Similar to other European settings, the UK has had rising non-vaccine serotype invasive pneumococcal disease, most notably in older adults, since introducing a 13-valent pneumococcal conjugate vaccine to the paediatric immunisation schedule. Such impacts of serotype replacement have not been reported in the USA, where incidence of non-vaccine serotype invasive pneumococcal disease in young children and older people has been stable since the introduction of the same vaccine. Here, we explore factors that have been suggested to account for these differences, including surveillance practices, transmission dynamics, population risk factors, and pathogen evolution. We contend that none of these factors individually appears sufficient to account for the observed differences. Assessing the existing evidence, we define priorities for research and data collection to discern causes and inform future pneumococcal vaccine policy.