The combination of HPLC and MS has become the most valuable analytical tool to determine the identity and purity of a drug substance in the drug discovery arena over the past decade. This article describes different LC/MS configurations and their broad applicability to meet the fundamental analytical requirements involved in discovering new drugs. In addition, the value of chemiluminescence nitrogen detection for absolute purity determination and the convenience of CE as an orthogonal separation technique to HPLC are also discussed. In summary, LC/MS-based methodologies that implicate automation, various levels of throughput and open access systems have proved to be an integral part of the drug discovery process. As a result, the paradigm of high-quality/-quantity information is fulfilled in a timely fashion.