In bacteria, a major resistance mechanism to β-lactam antibiotics is the production of one or more β-lactamase enzymes. β-Lactamases belong to two structurally and mechanistically unrelated families of enzymes, serine-β-lactamases (SBLs; classes A, C, and D) and metallo-β-lactamases (MBLs; class B). The interest in discovering novel inhibitors has recently renewed to counter the threat from newer β-lactamases, such as the extended spectrum β-lactamases (ESBLs) and carbapenemases, that are not inhibited by classical SBL inhibitors. Although resistance development is an ordinary evolutionary process, it has been significantly accelerated by the widespread and uncontrolled misuse of antibiotics and, nowadays, it represents one of the most relevant threats for human health.This Special Issue includes full research articles, brief reports and reviews focused on the targeting of b-lactamases to fight bacterial drug resistance.[...].