Drug metabolism and pharmacokinetic studies have essential roles to play in all stages of the research and development process, ideally being involved from drug discovery through to post-marketing surveillance, because pharmacokinetic variability is the cause of major problems in drug development. The origins of these problems have been termed “pharmacokinetic defects” and include, among others, poor absorption, very short or very long half-life, enzyme inhibition and high first-pass effect. Traditionally, the significance of many of these has been realized only after extensive clinical development. Failure to take these into consideration can result in expensive delay or failure during development and make an approved drug vulnerable in the marketplace. The thoughtful inclusion of new feedback loops offers the prospect of improved decision-making at various stages of drug development. These should be based on quality metabolic and pharmacokinetic data and exploit the opportunities which the new biology offers to “humanize” drug development by predicting human metabolic pathways, anticipating kinetic variability in human populations and understanding mechanisms of toxicity. Such improved decision making should contribute to enhanced time- and cost-efficiency of development and ultimately lead to safer, more easily used drugs.