Clinical and preclinical studies indicate that unbalanced systemic iron concentrations negatively affect bone health. Despite distinct underlying mechanisms, both iron deficiency and iron overload result in decreased bone mineral density and an increased fracture risk, the latter being associated with higher morbidity and mortality rates. In iron deficiency, both osteoclasts and osteoblasts suffer from the lack of iron to efficiently execute metabolic processes and produce enough energy for bone resorption and formation, respectively. In contrast, iron overload inhibits osteoblast differentiation and function by increasing the production of reactive oxygen species and lipid peroxidation, while it stimulates osteoclastogenesis and bone resorption. Besides the direct effects of iron on bone, regulators of systemic iron homeostasis have also been shown to impact bone homeostasis. This chapter summarizes current knowledge on the regulation of bone cell function and bone homeostasis by iron. Furthermore, it discusses new avenues for the treatment of iron-related bone loss.