There have been numerous studies to show that many of the medicines used in children are used off-label or are unlicensed for use in children. When children are prescribed unlicensed and off-label medications, some people may see them as unknowing participants in informal and uncontrolled experiments. However, the licensing status of a drug can be seen as a by-product of the real issues: the safety, efficacy and quality of these medicines in the current licensing system. It is important to conduct research in order to provide high quality data regarding safety and efficacy to support evidence-based paediatric prescribing. Clinical trials will always be an invaluable means of acquiring vital information about a drug; but when it comes to children, we may find that these trials are not always practical for technical, ethical and financial reasons; therefore, it is important to explore other methodologies in paediatric medicines research. Pharmacoepidemiological and prospective cohort studies could provide vital safety and efficacy data on paediatric medicines; however, resources need to be invested in the methodological research. Paediatric drug formulation research is under-resourced and under-valued, and, unfortunately, fatal and serious adverse reactions due to inappropriate formulations have been reported in many instances. Paediatric medication is a complex problem; we need to use all available tools for research on safety, efficacy and formulation. The reason for lack of progress in paediatric drug research is most likely due to lack of resources and research capacity. The industry and government should work together and invest more money in paediatric drug research. Finally, regulatory authorities, healthcare professionals and academics need to rethink the research strategy in order to provide better medicines for children.