Calcification is the deposition of minerals, mainly hydroxyapatite, inside the cell or in the extracellular matrix. Physiological calcification is central for many aspects of development including skeletal and tooth growth; conversely, pathological mineralization occurs in soft tissues and is significantly associated with malfunction and impairment of the tissue where it is located. Various mechanisms have been proposed to explain calcification. However, this research area lacks a more integrative, systemic, and global perspective that could explain both physiological and pathological processes. In this review, we propose such an integrated explanation. Hydrogen sulfide (H ₂ S) is a newly recognized multifunctional gasotransmitters and tis actions have been studied in different physiological and pathological contexts, but little is known about its potential role on calcification. Interestingly, we found that H ₂ S promotes calcification under physiological conditions and has an inhibitory effect on pathological processes. This makes H ₂ S a potential therapy for diseases related to pathological calcification. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.