The combination of high‐performance liquid chromatography and mass spectrometry (LC/MS) has had a significant impact on drug development over the past decade. Continual improvements in LC/MS interface technologies combined with powerful features for structure analysis, qualitative and quantitative, have resulted in a widened scope of application. These improvements coincided with breakthroughs in combinatorial chemistry, molecular biology, and an overall industry trend of accelerated development. New technologies have created a situation where the rate of sample generation far exceeds the rate of sample analysis. As a result, new paradigms for the analysis of drugs and related substances have been developed. The growth in LC/MS applications has been extensive, with retention time and molecular weight emerging as essential analytical features from drug target to product. LC/MS‐based methodologies that involve automation, predictive or surrogate models, and open access systems have become a permanent fixture in the drug development landscape. An iterative cycle of “what is it?” and “how much is there?” continues to fuel the tremendous growth of LC/MS in the pharmaceutical industry. During this time, LC/MS has become widely accepted as an integral part of the drug development process. This review describes the utility of LC/MS techniques for accelerated drug development and provides a perspective on the significant changes in strategies for pharmaceutical analysis. Future applications of LC/MS technologies for accelerated drug development and emerging industry trends are also discussed. © 1999 John Wiley & Sons, Inc., Mass Spec Rev 18: 187–279, 1999