Orthodontic tooth movement and bone remodeling activity are dependent on systemic factors such as nutritional factors, metabolic bone diseases, age, and use of drugs. Therefore, a comprehensive review of the effects of these factors on orthodontic tooth movement is attempted in this article. Systemic hormones such as estrogen, androgen, and calcitonin are associated with an increase in bone mineral content, bone mass, and a decrease in the rate of bone resorption. Consequently, they could delay orthodontic tooth movement. On the contrary, thyroid hormones and corticosteroids might be involved in a more rapid orthodontic tooth movement during orthodontic therapy and have a less stable orthodontic result. Drugs such as bisphosphonates, vitamin D metabolites, and fluorides can probably cause a reduction of tooth movement after the orthodontic force is applied. Nonsteroidal anti-inflammatory drugs have also been shown to reduce bone resorption. Long-term administration of these drugs may therefore delay the necessary bone response to respective tooth-borne pressure and should not be administered for long periods of time to patients undergoing orthodontic tooth movement. Attention has also been focused on the effects of prostaglandins and leukotrienes in orthodontic tooth movement. It seems that they might have future clinical applications that could result in enhanced tooth movement. The use of the above drugs should be considered by every dentist in evaluating the treatment time and in planning treatment when tooth movement is attempted.