Nearly two decades have passed since a paradoxical reaction in the orofacial region to some bone modifying agents and other drugs was recognized, namely medication-related osteonecrosis of the jaw (MRONJ). The aim of this manuscript was to critically review published data on MRONJ to provide an update on key terminology, concepts, and current trends in terms of prevention and diagnosis. In addition, our objective was to examine and evaluate the therapeutic options available for MRONJ. The authors perused the most relevant literature relating to MRONJ through a search in textbooks and published articles included in several databases for the years 2003–2021. A comprehensive update of the current understanding of these matters was elaborated, addressing these topics and identifying relevant gaps of knowledge. This review describes our updated view of the previous thematic blocks, highlights our current clinical directions, and emphasizes controversial aspects and barriers that may lead to extending the accumulating body of evidence related to this severe treatment sequela.