In humans, physiological bone and tooth mineralization is a complex cell-mediated process. Prerequisites for proper mineralization include sufficient amounts of minerals (calcium and phosphate [Pi]) to initiate the formation and the growth of apatite crystals and adequate amounts of mineralization inhibitors, such as pyrophosphate (PPi), to prevent uncontrolled extraskeletal mineralization. In this review, we provide an overview of the genetics of human disorders of mineralization, focusing on Pi and PPi metabolism and transport diseases, as the Pi/PPi ratio is an important determinant of crystal production in vivo. Variants in genes implicated in the homeostasis of this ratio may lead to a systemic or local increased Pi/PPi ratio, either by increasing the Pi concentration or by decreasing the PPi concentration, resulting in ectopic calcifications; conversely, variants may lead to a decreased Pi/PPi ratio, resulting in defective mineralization. Owing to the implication of common pathways and, occasionally, to some extent of clinical overlap, an accurate diagnosis and understanding of the pathophysiology of these disorders may be challenging. However, precise molecular characterization of these conditions not only facilitates their diagnosis, but also helps to gather evidence regarding the pathophysiology and phenotype-genotype correlation to improve medical care and develop innovative therapeutics.