Bone cancer is common and difficult to treat. Current bone-targeted therapies include radiation and bisphosphonates. Both treatments can provide pain relief, but neither has been shown to prolong survival. Because bisphosphonates are osteoclast-targeted therapies, they do not exhibit significant tumor-killing properties in humans. Often, patients with asymptomatic skeletal metastases are treated with observation. New treatments are needed for patients known to have bone metastases and those who are at high risk for having bone metastases develop. Enzyme prodrug gene therapy treatment strategies currently are being explored for their potential benefit in designing novel therapies for bone cancer.