Comparing genomic and biological characteristics across multiple species is essential to using model systems to investigate the molecular and cellular mechanisms underlying human biology and disease and to translate mechanistic insights from studies in model organisms for clinical applications. Building a scalable knowledge commons platform that supports cross-species comparison of rich, expertly curated knowledge regarding gene function, phenotype, and disease associations available for model organisms and humans is the primary mission of the Alliance of Genome Resources (the Alliance). The Alliance is a consortium of seven model organism knowledgebases (mouse, rat, yeast, nematode, zebrafish, frog, fruit fly) and the Gene Ontology resource. The Alliance uses a common set of gene ortholog assertions as the basis for comparing biological annotations across the organisms represented in the Alliance. The major types of knowledge associated with genes that are represented in the Alliance database currently include gene function, phenotypic alleles and variants, human disease associations, pathways, gene expression, and both protein–protein and genetic interactions. The Alliance has enhanced the ability of researchers to easily compare biological annotations for common data types across model organisms and human through the implementation of shared programmatic access mechanisms, data-specific web pages with a unified “look and feel”, and interactive user interfaces specifically designed to support comparative biology. The modular infrastructure developed by the Alliance allows the resource to serve as an extensible “knowledge commons” capable of expanding to accommodate additional model organisms.