Metabonomics is an emerging technology that enables rapid in vivo screening for toxicity, disease state, or drug efficacy. The technology combines the power of high-resolution nuclear magnetic resonance (NMR) techniques with statistical data analysis methods to rapidly evaluate the metabolic “status” of an animal. Complimentary to other profiling technologies like proteomics and genomics, metabonomics provides a fingerprint of the small-molecules contained in a given biofluid through the time course of a study. This article reviews the steps in implementing a metabonomics-based screening program from study design through data analysis. While metabonomics is still a relatively new technology in comparison to the other “omics”, published results from metabonomics studies demonstrate its potential impact in the drug discovery process by enabling the incorporation of safety endpoints much earlier in the drug discovery process, reducing the likelihood (and cost) of later stage attrition.