The skeletal changes associated with systemic retinoid therapy reflect the influence of retinoids on differentiating systems. Although skin is usually the intended target, treatment with retinoids often results in abnormalities of ossification and calcification. The effects of retinoids on bone may be profound and include progressive calcification of ligaments and tendon insertions, premature fusion of epiphyses, modeling abnormalities of long bones, and perhaps osteoporosis. Although it has been known since 1933 that vitamin A cause bone abnormalities, the mechanism of this effect has been elusive. Recent work suggests a possible relationship of the retinoids with several cytokines, which results in enhanced maturation of the preosteoclast. The increasing number of significant bone changes, including posterior lumbar vertebral osteophytosis, make skeletal toxicity the principle risk factor of chronic systemic retinoid therapy.