Natural products have evolved, at least in part, to bind to biological macromolecules, particularly proteins. As a result, natural products are able to interact with many specific targets within the cell. Indeed for many years this has been central in the drug development process. Today, however, natural products are finding increasing use as probes to interrogate biological systems as part of chemical genomics and related research. In order to demonstrate the utility of natural products in these efforts, the biological activities of many of the major classes of natural products is discussed, according to the cellular organelle and localisation of their specific molecular targets. Emphasis is given to newly discovered compounds and activities that either provide interesting insights into a specific biological function, or that form the basis for potentially new therapeutic approaches. © The Royal Society of Chemistry.