Infectious diseases, also known as communicable diseases, refer to a full range of maladies caused by pathogen invasion to the host body. Host response towards an infectious pathogen varies between individuals, and can be defined by responses from asymptomatic to lethal. Host response to infectious pathogens is considered as a complex trait controlled by gene–gene (host–pathogen) and gene–environment interactions, leading to the extensive phenotypic variations between individuals. With the advancement of the human genome mapping approaches and tools, various genome-wide association studies (GWAS) were performed, aimed at mapping the genetic basis underlying host susceptibility towards infectious pathogens. In parallel, immense efforts were invested in enhancing the genetic mapping resolution and gene-cloning efficacy, using advanced mouse models including advanced intercross lines; outbred populations; consomic, congenic; and recombinant inbred lines. Notwithstanding the evident advances achieved using these mouse models, the genetic diversity was low and quantitative trait loci (QTL) mapping resolution was inadequate. Consequently, the Collaborative Cross (CC) mouse model was established by full-reciprocal mating of eight divergent founder strains of mice (A/J, C57BL/6J, 129S1/SvImJ, NOD/LtJ, NZO/HiLtJ, CAST/Ei, PWK/PhJ, and WSB/EiJ) generating a next-generation mouse genetic reference population (CC lines). Presently, the CC mouse model population comprises a set of about 200 recombinant inbred CC lines exhibiting a unique high genetic diversity and which are accessible for multidisciplinary studies. The CC mouse model efficacy was validated by various studies in our lab and others, accomplishing high-resolution (< 1 MB) QTL genomic mapping for a variety of complex traits, using about 50 CC lines (3–4 mice per line). Herein, we present a number of studies demonstrating the power of the CC mouse model, which has been utilized in our lab for mapping the genetic basis of host susceptibility to various infectious pathogens. These include Aspergillus fumigatus, Klebsiella pneumoniae, Porphyromonas gingivalis and Fusobacterium nucleatum (causing oral mixed infection), Pseudomonas aeruginosa, and the bacterial toxins Lipopolysaccharide and Lipoteichoic acid.