Biomarker-guided screening is a multidisciplinary approach that can be used to facilitate early drug discovery from natural products. By integrating powerful genomic tools and the rapidly expanding knowledge of biomarkers, the screening systematically identifies compounds with therapeutic potential from herbal medicines. Compounds identified through this screening are associated with biomarkers, which provide unique bases for the further characterization of the therapeutic potential, as well as biological mechanisms, of these molecules. This feature review outlines the basic concept of biomarker-guided screening, and describes two proof-of-principle studies, which demonstrated the promise and technical feasibility of this methodology. The scope and limitations of this method are also discussed.