In vivo influenza infection models are critical for understanding viral dynamics and host responses during infection. Mouse models are extremely useful for infection studies requiring a high number of test animals. The vast array of gene knockout mice available is particularly helpful in investigating a particular gene's contributions to infection. Thus, more in vivo scientific experimentation of influenza has been done on mice than any other animal model. Here, we describe the technique of intranasal inoculation of mice and methods for assessing the severity of disease and humane endpoints, and discuss data acquired from infection of female C57BL/6J mice.