Sesquiterpene lactones (STLs) are a prominent group of plant secondary metabolites predominantly found in the Asteraceae family and have multiple ecological roles and medicinal applications. This review describes the ecological significance of STLs, highlighting their roles in plant defense mechanisms against herbivory and as phytotoxins, alongside their function as environmental signaling molecules. We also cover the substantial role of STLs in medicine and their mode of action in health and disease. We discuss the biosynthetic pathways and the various modifications that make STLs one of the most diverse groups of metabolites. Finally, we discuss methods in identifying and predicting STL biosynthesis pathways.