Ecologists have long searched for an explanation as to why some plant invaders become much more dominant in their naturalized range than in their native range, and, accordingly, several non-exclusive ecological hypotheses have been proposed. Recently, a biochemical explanation was proposed--the "novel weapons hypothesis"--based on findings that Centaurea diffusa and Centaurea maculosa produce bioactive compounds (weapons) that are more active against naïve plant species in the introduced range than against co-evolved species in the native range. In this Opinion article, we revise and expand this biochemical hypothesis and discuss experimental and conceptual advances and limitations.