摘要The Collaborative Cross (CC) mouse model is a next-generation mouse genetic refer-ence population (GRP) designated for a high-resolution quantitative trait loci (QTL) mapping of complex traits during health and disease. The CC lines were generated from reciprocal crosses of eight divergent mouse founder strains composed of five classical and three wild-derived strains. Complex traits are defined to be controlled by variations within multiple genes and the gene/environment interactions. In this article, we introduce and present variety of protocols and results of studying the host response to infectious and chronic diseases, including type 2 diabetes and meta-bolic diseases, body composition, immune response, colorectal cancer, susceptibility to Aspergillus fumigatus, Klebsiella pneumoniae, Pseudomonas aeruginosa, sepsis, and mixed infections of Porphyromonas gingivalis and Fusobacterium nucleatum, which were conducted at our laboratory using the CC mouse population. These traits are observed at multiple levels of the body systems, including metabolism, body weight, immune profile, susceptibility or resistance to the development and progress of infectious or chronic diseases. Herein, we present full protocols and step-by-step methods, implemented in our laboratory for the phenotypic and genotypic charac-terization of the different CC lines, mapping the gene underlying the host response to these infections and chronic diseases. The CC mouse model is a unique and powerful GRP for dissecting the host genetic architectures underlying complex traits, including chronic and infectious diseases.