A phenotyping study records physiologic or morphologic changes in an experimental animal resulting from an intervention. In mice, this intervention is most frequently genetic, but it may be any type of experimental manipulation. Accurate representation of the human condition under study is essential if the model is to yield useful conclusions. In this review, general approaches to the design of phenotyping studies are considered. These approaches take into account major sources of reduced model validity, such as unexpected phenotypic variation in mice, evolutionary divergence between mice and humans, unanticipated sources of variation, and common design errors. As poor design is the most common reason why studies fail to yield enduring results, emphasis is placed on reduction of bias, sampling, controlled study design, and appropriate statistical analysis.