Natural products have played an important role in anticancer drug development for many decades. A recent review analyzing clinically approved anticancer drugs in Western countries and Japan during a twenty-five year period from 1981 to 2006 showed that, under the class of “non-biologicals/vaccines”, 63 of 81 (77.8%) anticancer drugs were either natural products or their derivatives, or synthesized molecules based on natural product pharmacophores. As part of a collaborative, multi-disciplinary approach to the discovery of new naturally occurring anticancer drugs, two medicinal plants, namely, Hyptis brevipes and Vitex quinata, collected in Indonesia, were selected for further investigation.The chloroform-soluble extract of a sample of the entire plant of H. brevipes showed activity against the MCF-7 human breast cancer cell line. Bioassay-guided fractionation and purification of the CHCl3-soluble extract of H. brevipes led to the isolation of six new 5,6-dihydropyrone derivatives, namely, brevipolides A-F (342-346), together with seven known compounds. Brevipolides A-F (342-346), and a previously known 5,6-dihydropyrone derivative (347), were assigned with the absolute configuration, 5R, 6S, 7S, and 9S, as elucidated by analysis of data obtained from their CD spectra and by Mosher ester reactions. Brevipolides B and D, as well as compound 347 exhibited ED50 values of 6.1, 6.7 and 3.6 µM against MCF-7 cells. Brevipolides A, B, and F, and compound 349 (the known 5,6,3′-trihydroxy-3,7,4′-trimethoxyflavone) gave ED50 values of 5.8, 6.1 7.5, and 3.6 µM against HT-29 cells, respectively. However, no significant cytotoxicity was found against Lu1 cells for any of the compounds isolated. When these compounds were subjected to evaluation in a panel of mechanism-based in vitro assays, compound 347 were found to be active in an enzyme-based ELISA NF-κB p50 assay, with an ED50 value of 15.3 µM. In a mitochondrial transmembrane potential assay, brevioplide C, compounds 348 and 349 showed ED50 values of 8.5, 75, and 310 nM, respectively. However, no potent activity was found in a proteasome inhibition assay for any of the isolated compounds.A phytochemical investigation of the chloroform-soluble and ethyl acetate-soluble extracts of the leaves of V. quinata led to the isolation of a new δ-truxinate derivative (378) and a new prostaglandin-like octadecanoid (379), together with 12 known compounds including flavonoids and quinic acid derivatives. All the isolates were tested in a panel of human cancer cells, and (S)-5-hydroxy-7,4′-dimethoxyflavanone (384) was found to be an active principle with ED50 values of 6.7, 4.7, and 1.1 µM against LNCaP (hormone-dependent prostate cancer), Lu1 (human lung cancer), and MCF-7 (human breast cancer) cell lines, respectively. Compounds 382 and 384-390 were tested in an enzyme-based ELISA NF-κB p65 assay to evaluate their potential in inhibiting the binding of NF-κB to DNA. Compounds 382, 384, 385, and 390 showed activity, with ED50 values of 22.8, 54.3, 17.8, 10.3 µM, respectively.