To elucidate the genetic influences contributing to susceptibility to seizure disorders, researchers have long used selected lines and inbred strains of rodents. In recent years, the use of genetically altered mice as models of complex human disease has revolutionized biomedical research into the genetics of disease pathogenesis and potential therapeutic interventions. In particular, the study of transgenic and gene-deleted (knockout) mice can provide important insights into the in vivo function and interaction of specific gene products. While a variety of inbred mouse mutations have been used to directly evaluate the genetic basis of seizure disorders, data obtained from such genetically altered mice must be interpreted carefully. An increasing number of scientific articles have reported that the phenotype of a given single gene mutation in mice can be modulated by the genetic background of the inbred strain in which the mutation is maintained. This effect is attributable to so-called modifier genes, which act in combination with the causative gene. In this review, the author points out the importance of considering the genetic background of the strain used to create these animal models, the potential problems with interpretation of phenotype, and solutions to selecting an appropriate mouse model of experimental epilepsy. Despite these potential limitations, knockout mice provide a powerful tool for understanding the genetic and neurobiological mechanisms contributing to experimental epilepsy.