We propose to create the Stanford PharmacoGenetic Knowledge Base (PharmGKB), an integrated data resource to support the NIGMS Pharmacogenetic Research Network and Database Initiative. This initiative will focus on how genetic variation contributes to variation in the response to drugs, and will produce data from a wide range of sources. The PharmGKB will therefore interlink genomic, molecular, cellular and clinical information about gene systems important for modulating drug responses. The PharmGKB is based on a powerful hierarchical data representation system that allows the data model to change as new knowledge is learned, while ensuring the security and stability of the data with a relational database foundation. Our proposal defines an interactive process for defining a data model, creating automated systems for data submission, integrating the PharmGKB with other biological and clinical data resources, and creating a robust interface to the data and to the associated analytic tools. Finally, we outline a research plan that uses the PharmGKB to (1) address difficult data modeling challenges that arise in the course of building the resource, (2) study the user interface requirements of a database with such a wide range of information sources, and (3) model and analyze the structural variations of proteins to shed light on the molecular consequences of genetic variation. The PharmGKB will respect the absolute confidentiality of genetic information from individuals.