While the human genome project is likely to lead to fundamental changes in our understanding of disease causation and our ability to screen for disease predisposition and treatment responsiveness, the current healthcare system is not properly aligned to ensure the proper use of these advances. As the pace of genetic technology development increases and new pharmacogenetic drugs and gene-based diagnostic tests increasingly impact providers, patients, health plans, payers and employers, it will be crucial to develop an evidence-based framework by which to evaluate these new tests and treatments. In order to increase the level of evidence available and allow for informed decisions in the face of strong marketing and advocacy forces, the authors suggest the development of one (or more) large clinical networks with the purpose of systematically evaluating the clinical effectiveness of new genomic applications, including pharmaceuticals and gene-based diagnostic tests, in ‘real world’ settings.