The perpetual evolution of drug-resistant microbes, the overwhelming burden of acquired immune suppression due to HIV, the emergence or re-emergence of various pathogens (West Nile virus, pandemic influenza, Creutzfeld-Jacob disease), and increased fears of bioterrorism has drawn a great deal of new attention to infectious diseases. The pathogenesis of infection is characterized by complex interactions of potentially virulent microorganisms with host genetic and acquired factors. Chemical mutagenesis of the mouse genome provides a robust method to unravel this challenging problem. To deepen our understanding of the natural host response to pathogens, our team and others are interrogating the mouse genome to define genes that are crucial to the defense against infectious diseases (pathogen recognition, viral defense, bacterial defense, prion infection). In this review we highlight the current progress of these efforts and propose a toolbox for other groups that are interested in this endeavor.