Nanotechnology is a global industry producing a large variety of engineered nanomaterials (ENMs) for use in virtually every industry sector. Quantum dots (QDs) are ENMs with attractive semiconductor and fluorescent properties and commonly consist of a cadmium and selenium (CdSe) core surrounded by a zinc sulfide (Zn/S) shell. QDs have applications in biomedical research and potentially medicine as imaging tools and have multiple uses in electronics and energy industries. Silver nanoparticles (AgNPs) are composed of silver atoms and sometimes include other metals such as gold. AgNPs have been incorporated into numerous products as an antimicrobial agent. While these ENMs have beneficial uses, they have been shown to induce lung inflammation and toxicity in rodent models following pulmonary exposures. However, most QD and AgNP toxicity studies to date have only used one strain of mouse or rat and thus have not addressed the role of genetic variability as a potential modulator of susceptibility. My dissertation was primarily focused on investigating the role of genetic background as a determinant of susceptibility to QD- and AgNP-induced lung inflammation and toxicity utilizing multi-strain mouse models. We found substantial inter-strain variation in susceptibility to QD- and AgNP-induced pulmonary inflammatory responses across the Collaborative Cross (CC) founder mouse strains. Over the last decade, the CC has created a panel of recombinant inbred (RI) mouse strains from eight genetically diverse founder strains to facilitate genetic mapping studies. Having established variability among the CC founder strains, we characterized the QD inflammatory response in a panel of CC RI inbred mouse strains in collaboration with researchers at the UNC. In collaboration with researchers at NYU we characterized the AgNP inflammatory response in 17 additional mouse strains (25 total strains). We used genome-wide association (GWA) mapping to identify genomic regions associated with QD- and AgNP-induced lung inflammation and toxicity containing candidate susceptibility genes that could modulate QD and AgNP responses and provide mechanistic insight. We also investigated the effects of QDs on lung mechanics and house dust mite (HDM) induced allergic airway disease in CC founder mouse strains we found initially to be more (A/J) and less (C57BL/6J) susceptible to QD-induced lung inflammation. Our results indicated that A/J mice were more susceptible to QD-induced changes lung mechanics. In addition, co-exposure to HDM+QDs enhanced cytokine production in A/J mice where HDM exposure alone did not result in significant increases and A/J mice had more lung type 2 innate lymphoid cells (ILC2s) than C57BL/6J mice. Significant inverse associations between glutathione and different endpoints across multiple studies highlighting the importance of redox balance in ENM induced lung inflammation and toxicity. The findings from these studies have important regulatory implications for ENMs in that genetic background of test animal strain is important to consider in risk models such that safety standards ensure adequate protection for sensitive populations.