Most pharmacogenetic strategies to date have focused on the role of single genes in the regulation of drug activity and have made important steps towards the goal of optimizing therapy for individual patients. However, there is clear evidence that medication responses, like most common diseases, are under the control of a network of genes, each contributing to the patient's phenotype. The CREATE Pharmacogenetic Research Network (Comprehensive Research on Expressed Alleles in Therapeutic Evaluation) was funded in August 2001 as one of 4 additions to the existing NIH Pharmacogenetics Research Network (PGRN). In the subsequent three short years, CREATE has made significant contributions to the PGRN goals of publicly available pharmacogenetic knowledge, shared computational and analytical resources, defining the common goals and needs for the field, and communicating PGRN findings to foster translation and application of pharmacogenetic knowledge. CREATE brought together infrastructure for the evaluation of pathways regulating drug activity. This was achieved through the coordinated efforts of investigators and staff from Washington University with expertise in the fields of Genomics, Pharmacogenetics, Clinical Pharmacology, Bioinformatics, Computational Biology, Statistical Genetics, Population Genetics, Developmental Pharmacology, and Translational Research. Together they will evaluate the following general aims to develop validation strategies for applied pharmacokinetics. General aims 1. Identify polymorphisms in members of pathways regulating drug activity 2. Evaluate novel approaches to pathway dissection 3. Validate and functionally assess drug pathway variants 4. Establish drug pathways in human development Supported by Administrative, Bioinformatic/Biostatistical, and Colecular Pathology Cores, these aims are being achieved using human gastrointestinal cancer as a model system, as it is a common cause of death, has no clear prognostic tools to guide therapy, has readily accessible tissue available in the Molecular Pathology Core, and is treated with a small number of medications. This approach is allowing us to continue to make strong progress in our understanding of the role of genes in pharmacologic response.