Calcification of tissues involves the formation and deposition of calcium-containing crystals in the extracellular matrix (ECM). While this process is normal in bones, it becomes pathological when it occurs in cardiovascular and musculoskeletal soft tissues. Pathological calcification (PC) triggers detrimental pathways such as inflammation and oxidative stress, contributing to tissue damage and dysregulated tissue biomechanics, ultimately leading to severe complications and even death. The underlying mechanisms of PC remain elusive. Emerging evidence suggests a significant role of lysyl oxidases (LOX(L)) in PC. LOX(L) are a group of five enzymes involved in collagen cross-linking and ECM maturation. Beyond their classical role in bone mineralization, recent investigations propose new non-classical roles for LOX(L) that could be relevant in PC. In this review, we analyzed and summarized the functions of LOX(L) in cardiovascular and musculoskeletal PC, highlighting their deleterious roles in most studies. To date, specific inhibitors targeting LOX(L) isoforms are under development. New therapeutic tools targeting LOX(L) are warranted in PC and must avoid adverse effects on physiological bone mineralization.