Once a knockout allele generated by gene targeting has been introduced into the germline of a mouse, the primary concern is to efficiently screen the animal for mutant phenotypes. This is not necessarily a trivial exercise given the high frequency of unexpected or lack of phenotypes. With the number of published knockout mouse strains approaching 1000, considerable experience has accumulated with respect to these concerns. Some of the most obvious approaches involve developmental surveys at the morphological and histological levels, physiological studies, perturbation of homeostatic balances, introduction of stress or injury, and analysis of mutant organs, tissues and cells in vitro. However, the history of mouse genetics, which in itself can be termed the study of strain-dependent phenotype variability, tells us that as a backdrop to these approaches the genetic background onto which the targeted allele is placed can cause considerable variation in phenotype. This variation can present itself as completely different phenotypes, as variations in penetrance of phenotype, or as variable expressivity of phenotype.