The keystone species concept provides a valuable framework for integrating findings across traditional disciplines that scale from the cellular level (chemical defense and chemosensory reception) and the organismal level (behavioral traits) to the community level (species interactions). Select bioactive compounds cause disproportionately large effects by connecting such seemingly disparate processes as microbial loop dynamics and apex predation. Outstanding examples of these “molecules of keystone significance” draw on four distinct compounds: dimethylsulfoniopropionate, saxitoxin, tetrodotoxin, and pyrrolizidine alkaloids. Through convergent evolution, they inform phylogenetically diverse species; initiate major trophic cascades; and structure respective communities within terrestrial, freshwater, coastal-ocean, and open-ocean environments. Their relevance to conservation biology involves the protection of threatened species or habitats in the face of natural- and human-induced disturbances.