As a group, strains of laboratory mice carrying Alzheimer's disease (AD)-related transgenes are currently the most widely studied animal models of AD. Many AD mouse models carrying the same or similar transgene constructs demonstrate strikingly different phenotypic responses to transgene expression, mimicking the apparent genetic complexity of AD pathogenesis seen in the human population. Genetic differences between the numerous mouse model strains used for AD research can significantly affect correct interpretation and cross-comparison of experimental findings, making genetic background an important consideration for all work in mouse models of AD. Furthermore, because of the potential for discovering novel genetic modifiers of AD pathogenesis, the effects of genetic background on AD phenotypes in the mouse can prove a worthwhile subject of study in their own right. This review discusses the implications of genetic modifiers for mouse and human AD research, and summarizes recent findings identifying significant roles for genetic background in modifying important phenotypes in AD mouse models, including premature death, amyloid deposition, tau hyperphosphorylation, and responsiveness to environmental or treatment interventions.