In the past three decades, ADME sciences have become an integral component of the drug discovery and development process. At the same time, the field has continued to evolve, thus, requiring ADME scientists to be knowledgeable of and engage with diverse aspects of drug assessment: from pharmacology to toxicology, and from in silico modeling to in vitro models and finally in vivo models. Progress in this field requires deliberate exposure to different aspects of ADME; however, this task can seem daunting in the current age of mass information. We hope this review provides a focused and brief summary of a wide array of critical advances over the past year and explains the relevance of this research (Table 1). We divided the articles into categories of (1) drug optimization, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation. This annual review is the fourth of its kind (Baillie et al. 2016; Khojasteh et al. 2017, 2018). We have followed the same format we used in previous years in terms of the selection of articles and the authoring of each section. This effort in itself also continues to evolve. I am pleased that Rietjens, Miller, and Mitra have again contributed to this annual review. We would like to welcome Namandjé N. Bumpus, James P. Driscoll, and Donglu Zhang as authors for this year’s issue. We strive to maintain a balance of authors from academic and industry settings. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. Cyrus Khojasteh, on behalf of the authors.