In vivo models represent important resources for investigating the pathophysiological mechanisms underlying inherited disorders and for preclinical translational studies that may include the assessment of new treatments. In the study of skeletal diseases, which may affect multiple cell types or multiple organs, in vivo models provide specific advantages over in vitro or ex vivo models, which are limited to the investigation of isolated systems. Mice are a popular choice for developing such in vivo mammalian models, as they have a genome that shares ∼85% identity to that of man, and have many physiological systems that are similar to those in man. Moreover, a number of methods have been developed to alter genes in the mouse, thereby generating models for human diseases, which may be due to loss- or gain-of-function mutations. These methods, which have been used to generate germline mutations in the mouse genome, include the following: chemical mutagenesis; conventional, conditional, and inducible knock-out models; knock-in models, transgenic models, and genome editing. This chapter reviews some of these different strategies as well as several mouse models that have been successfully generated by these methods for human hereditary disorders of mineral and skeletal homeostasis. In addition, some of the advances that have been made in our understanding of the mechanisms of these human diseases are described by investigations of these mouse models.