Covering: up to June 2017Natural products and endogenous metabolites engage specific targets within tissues and cells through complex mechanisms. This review examines the extent to which natural systems have adopted the Paal-Knorr reaction to engage nucleophilic amine groups within biological targets. Current understanding of this mode of reactivity is limited by only a few examples of this reaction in a biological context. This highlight is intended to stimulate the scientific community to identify potential research directions and applications of the Paal-Knorr reaction in native and engineered biological systems.