The cure rates in cancer chemotherapy are affected by the development of drug resistance and severe side effects. Due to these limitations, there is an urgent need for improved therapeutics. Bioactive compounds from medicinal plants represent a valuable resource for novel anticancer drugs. To gain a systematic approach, we established a library of 531 cytotoxic natural products derived from traditional Chinese medicine. Cellular and pharmacogenomic profiling was performed for the 10 most cytotoxic natural products. One of these compounds, helebrin, was analyzed in more detail. The IC50 values for hellebrin of 60 NCI cell lines were associated with the microarray-based expression of 9,706 genes. By hierarchical cluster analyses, candidate genes were identified which significantly predicted sensitivity or resistance of cell lines to hellebrin.