Leptin and its actions in bone came to prominence in 2000, with the publication of two landmark articles identifying a novel interaction between energy and bone homeostasis, as well as a novel hypothalamic circuit to the skeleton. However, they also revealed the dichotomous nature of leptin's effect on the skeleton. Subsequent research has increased understanding of the factors critical to interpretation of the leptin-bone signaling. These include opposing effects in cortical and cancellous bone, central and peripheral effects, involvement of other neural and endocrine factors, and leptin receptor polymorphisms in human populations. It is clear that leptin can markedly influence the regulation of bone mass, and that study of this pathway continues to increase our knowledge of the biology of skeletal tissue and its interactions with other tissues. However, this relationship is complex and requires careful interpretation.