Inflammation is a complex phenomenon necessary in human defense mechanisms but also involved in the development of some human diseases. The discovery of cyclooxygenase-2 (COX- 2) improved the pharmacology of nonsteroidal anti-inflammatory drugs (NSAID) giving a clear mechanism for prostaglandin regulation in vivo and providing a new target for the development of COX-2-selective drugs without gastrointestinal side-effects. Keeping in view the importance of this pharmacological class, several literature reports have underlined the impact of these antiinflammatory compounds in therapeutics. The present review considers the most recently published literature concerning COX-2 inhibitors until 2016. Through a wide chemical classification, the last developments concerning this therapeutic family by highlighting structure-activity relationships insights and mechanisms are presented. A summary of the principal adverse effects observed and an overview of the new potential therapeutic indications for COX-2 inhibitors are also reported.