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About 25 years ago, a fundamental change in the conduct of pharma- ceutical research occurred: the baton was passed from the chemist to the biologist as the driver of innovation. Previously, the biologist - who was first and foremost a pharmacologist and physiologist - was relegated to the role of testing new compounds synthesized by chemists. More recently, empowered by rapid progress in cell and molecular biology based understanding of disease, biologists developed the ability to formulate rational hypotheses of disease-relevant mechanisms and began to present the chemist with putative cellular targets that then became the starting point for drug discovery - inverting the previous sequence. Commonly, these targets were derived from a mechanistic physiological understanding of how biochemical pathways affect certain phenotypes. In parallel, the development of tools to determine molecular structure generated great enthusiasm for 'rational drug design'. As the limitations of this approach became disappointingly clear, the emphasis of drug discovery shifted to high-throughput, automated screening of as large and as diverse a collection of molecules as possible. This primary approach, initiated and driven by the biologist, is then followed by a dedicated, systematic effort to improve a 'hit' by the medicinal chemist. Highly potent, specific, and selective drugs thus developed, e.g. proton pump inhibitors, HMG-CoA reductase inhibitors, and serotonin re-uptake inhibitors, to name a few, have changed the face of medicine. Despite these dramatic strides, a critical dilemma remains: our medicines do not work well for everyone. As physicians in clinical practice will testify on the basis of daily experience, a medicine can be well- tolerated and dramatically effective for Patient A, only to be ineffective or

Genetics in drug discovery and development: challenge and promise of individualizing treatment in common complex diseases