The completed sequencing of genomes has forced upon us the challenge of understanding how the detailed information in the genome gives rise to the specific characteristics--phenotype--of the individual. This is crucial for understanding not only normal development but also, from a medical perspective, the genetic basis of disease. Much of the mammalian genome-to-phenotype relationship will be worked out in the mouse, for which powerful genetic-manipulation tools are available. Mouse imaging combined with powerful statistical methods has a unique and growing role to play in phenotyping genetically modified mice. This review outlines the challenges for image-based phenotyping, summarizes the current state of three-dimensional imaging technologies for the mouse, and highlights new opportunities in systems biology that are opened by imaging mice.