Technical Abstract: Plants synthesize a wide diversity of secondary products, many,if not most, of which have yet to be identified. Although massive effort has been expended on chemical elucidation of these compounds, there has been comparatively little research to determine their biological activities. Discovery of those compounds with useful biological activities can be approached as a random walk through the chemistry of the plant kingdom, or strategies can be employed to maximize research efforts. Ecological and ethnobotanical clues have been very useful in identifying plant species as likely sources of phytochemicals, as well as in suggesting medicinal and agricultural uses. After a species is identified, anatomical clues can be helpful in determining the location of compounds of interest within the plant. Many bioactive secondary compounds are secreted or sequestered within specialized structures or cells to protect the producing plant from autotoxic injury. Examinaton of the compounds secreted by the plant into the soil, its resin canals, or onto plant surfaces can accelerate the discovery of bioactive molecules. Similarly, highly bioactive compounds often accumulate in trichomes and trichome-like structures. Examples of anatomical localization of bioactive compounds by plants discussed in this chapter include sorgoleone and its analogues from Sorghum species, artemisiniin from Artemisia annua, and hypericin from various Hypericum species. Anatomical localization may also sometimes suggest the type of biological activities compounds may have.Perhaps the most costly aspect of natural product discovery has been the wasted effort in the rediscovery of known compounds.Use of informatics and modern analytical instrumentation such as LC-MS/MS and LC-NMR can minimize this aspect of dereplication.