The Editorial Board of the Medicinal Chemistry section of the journal Molecules publishes here its first Editorial, which has been prepared by highlighting, in sub-editorials of about one hundred words, some selected recently published articles that may have a profound impact on drug discovery and therapy. In particular, this editorial highlights new drug targets and mechanisms of action and new classes of drugs, as well as new therapeutic uses for known drugs or the involvement of known biological targets in new diseases. We also discuss some structural biology studies and new computational tools that may pave the way for the rational design or identification of more efficacious and safer drugs. Overall, the findings reported in these highlighted papers raise our hopes for the management of difficult-to-treat diseases that are posing a growing health threat, with new or repurposed drugs that overcome the limitations of currently applied therapies.