Skeletal metastases occur in many patients with different kinds of malignant tumors, especially in advance stage of breast cancer (in 47%-85% of patients), prostate cancer (33-85%), and lung cancer (32%-60%). The management of painful skeletal metastases is complicated and should be carried out by a multidisciplinary approach including conventional analgesics, antitumor therapy (chemo- and hormone therapy), osteoclast-inhibitory agents (bisphosphonates), corticosteroids, external-beam radiotherapy, surgery, and nuclear medicine therapy. The nuclear medicine therapy for palliation of pain from bone metastases is a systemic radionuclide therapy based on the use of radiopharmaceuticals. In several studies the efficacy of bone-seeking radiopharmaceuticals have been demonstrated in terms of pain reduction from diffuse skeletal metastases. In this review, we will summarize the current literature on bone-seeking radiopharmaceuticals for the treatment of painful bone metastases (Phosphorus-32, Strontium-89, Rhenium-186, Rhenium-188, Samarium-153, and Radium-223) and the combination therapy with biphosphonates and chemotherapy.