Hydrogen peroxide (HO), superoxide anion radical (O•), and other forms of reactive oxygen species (ROS) are produced by the vast majority of mammalian cells and can contribute both to cellular homeostasis and dysfunction. The NADPH oxidases (NOX) enzymes and the mitochondria electron transport chain (ETC) produce most of the cellular ROS. Multiple antioxidant systems prevent the accumulation of excessive amounts of ROS which cause damage to all cellular macromolecules. Many studies have examined the contribution of ROS to different bone cell types and to skeletal physiology and pathophysiology. Here, we discuss the role of HO and O• and their major enzymatic sources in osteoclasts and osteoblasts, the fundamentally different ways via which these cell types utilize mitochondrial derived HO for differentiation and function, and the molecular mechanisms that impact and are altered by ROS in these cells. Particular emphasis is placed on evidence obtained from mouse models describing the contribution of different sources of ROS or antioxidant enzymes to bone resorption and formation. Findings from studies using pharmacological or genetically modified mouse models indicate that an increase in HO and perhaps other ROS contribute to the loss of bone mass with aging and estrogen deficiency, the two most important causes of osteoporosis and increased fracture risk in humans.