<p>Choices in type and dosing of medications, in particular analgosedation, in pediatric severe traumatic brain injury (sTBI) are topics of debate leading to heterogeneous practice because of low level evidence. However, given the heterogeneity of the disease and patient population in combination with the highly regulated aspect of pediatric pharmacological studies, this is not surprising. This review provides a conceptual framework how pediatric pharmacotherapy, with a focus on analgosedation in sTBI, should shift to a more tailor-made approach. To that end, careful consideration of disease, drug and patient factors that ultimately determine safe and effective pharmacotherapy are necessary. Each of the aforementioned factors hold promising avenues to investigate in a collaborative manner and with alternative study designs to develop tailored pharmacological practices in children with sTBI. These avenues are explored in this educational review.</p>