Gene and/or pathway conservation across species implies essential functions for that gene or pathway in a particular biological response. Such conservation is particularly important in studies of model organisms, where one wishes to infer biology in one species, based on studies in another. In this respect, murine studies have been particularly informative for generating insights into human physiological and pathophysiological processes. Some biological systems are particularly susceptible to evolutionary change, however, as is the case with the innate immune system that must co-evolve with rapidly evolving pathogens. An understanding of evolutionary conservation and divergence in innate immune pathways across species can provide insights into both species-specific immune responses that are likely to be important for host defence, as well as limitations of model organisms for studies of innate immune processes relevant to human disease. In this chapter, we discuss genetic differences in human versus mouse innate immunity, as well as specific mechanisms that contribute to such differences. While we provide a broad overview of several innate immune gene families, we focus in more detail on the Toll-like receptor 4 pathway, which is involved in sensing lipopolysaccharide from Gram-negative bacteria.