The osteoclast represents one of the most highly specialized cells within the human body, which operates within a microenvironment of diverse cellular populations and matrix proteins. Moreover, the osteoclast directly effects and is affected by these surroundings in a delicate relationship of cellular differentiation, bone resorption, and controlled apoptosis. The result is the maintenance of adequate bone mass throughout life. Unsurprisingly, disturbances within this environment or the molecular regulation of normal osteoclast biology has profound effects on skeletal homeostasis and crippling physical manifestations. This review will summarize current literature describing normal and pathological osteoclast biology and highlight the benefits of osteoclast-targeted therapy to combat skeletal disorders.