Mouse models have enabled breakthroughs in our understanding of the immune system, but it has become increasingly popular to emphasize their shortcomings when translating observations to humans. This review provides a brief summary of mouse natural history, husbandry, and the pros and cons of pursuing basic research in mice versus humans. Opportunities are discussed for extending the predictive translational value of mouse research, with an emphasis on exploitation of a “dirty” mouse model that better mimics the diverse infectious history that is typical of most humans.