Over the past few years, despite the lack of approved pediatric labelling, dexmedetomidine’s (DEX) use has become more prevalent in pediatric clinical practice as well as in research trials. Its respiratory-sparing effects and bioavailability by various routes are only some of the valued features of DEX. In recent years the potential organ-protective effects of DEX, with the possibility for preserving neurocognitive function, has put it in the forefront of clinical and bench research. This comprehensive review focused on the pediatric literature but presents relevant, supporting adult and animal studies in order to detail the recent growing body of literature around the pharmacology, end-organ effects, organ-protective effects, alternative routes of administration, synergetic effects, and clinical applications, with considerations for the future.