Extracellular matrix mineralization is important for mechanical stability of the skeleton and for calcium and phosphate storage. Professional mineral-disposing cell types are hypertrophic chondrocytes, odontoblasts, ameloblasts and osteoblasts. Since ectopic mineralization causes tissue dysfunction mineralization inhibitors and promoting factors have to be kept in close balance. The most prominent inhibitors are fetuin-A, matrix-Gla-protein (MGP), SIGBLING proteins and pyrophosphate. In spite of their ubiquitous presence, their loss entails a specific rather than a stereotypic pattern of ectopic mineralization. Typical sites of pathological mineral accumulation are connective tissues, articular cartilage, and vessels. Associated common human pathologies are degenerative joint disorders and arteriosclerosis. This article gives a summary on what we have learned from different mouse models with pathologic mineralization phenotypes about the role of these inhibitors and the regulation of mineralization promoting factors.