There is a complex interplay between genetics and bone tissue, for both bone morphology and the ability to remodel. Understanding the genetic basis of bone traits in the adult skeleton facilitates the discovery of novel genes or pathways as therapeutic targets for low bone mass. To this end, a genetically diverse mouse population has been created by The Jackson Laboratory using eight Inbred Founder strains. These eight inbred strains were cross-bred for multiple generations to produce the Diversity Outbred (DO) mice, a population with random assortments of genes more closely modeling the human population. Using all eight Inbred Founder strains and the DO mice I investigated the effect of genetic diversity on bone phenotype and the response to mechanical loading. Specifically, the goals of this dissertation were to investigate 1) the effect of genetic diversity on bone phenotype across length scales, 2) the effect of genetic diversity on bone response to loading, and 3) the correlation of phenotype to loading response in genetically diverse populations. In Aim 1, I measured bone morphology, mechanical properties, material properties, lacunar morphology, and mineral composition of mouse bones from these two populations of genetic diversity. Additionally, I compared how intra-bone relationships varied in the two populations. Multi-scale cortical bone traits vary significantly with genetic background with heritability values ranging from 21% to 99%, indicating genetic control of bone traits across length scales. This investigation is the first to show that lacunar shape and number are highly heritable. Comparing the two populations of genetic diversity, the phenotypes of each DO mouse do not resemble that of single Inbred Founder but instead the outbred mice display hybrid phenotypes with the elimination of extreme values. Additionally, intra-bone relationships (e.g., ultimate force vs. cortical area) were mainly conserved in our two populations. In Aim 2, I mechanically loaded mice from the two populations of genetic diversity to assess the variation in bone response to loading. I showed the response to loading varies with genetic background and is highly heritable with heritability values ranging from 32% to 97%. All measurements of periosteal formation have a heritability value near or above 80%. On average, the DO population showed a more robust response to mechanical loading compared to the Inbred Founders with all DO mice having a net increase in all bone formation outcomes. In Aim 3, I combined the results from the two previous aims to explore the correlation between bone phenotype and the response to mechanical loading. Bone axial stiffness and lacunar traits correlate with the magnitude of loading outcomes. Stiffer bones and bones with more elongated lacunae respond more robustly to mechanical loading. From these correlations I developed a working model that intrinsic osteocyte mechanosensitivity – controlled at least partially by genetics – drives the morphology of bone to maintain a homeostatic mechanical strain state. The work of this thesis provides the groundwork and rationale to perform genome wide association studies (GWAS) or quantitative trait loci (QTL) analysis to identify candidate genes that regulate bone phenotype and the response to loading. Uncovering novel genes can provide new targets for therapeutics to not just stop bone loss but increase bone mass, especially in patients where weight-bearing exercise is unsafe or less feasible.