Bisphosphonates are extensively used to treat cancer-induced bone disease in a range of solid tumours and multiple myeloma, where they reduce the incidence of skeletal related events and improve patients' quality of life. Recent reports indicate that bisphosphonates may also prevent recurrence of breast cancer at peripheral sites, suggesting that these drugs may have anti-tumour effects outside the skeleton. Anti-tumour effects of several bisphosphonates have been reported in a range of tumour cell types in vitro. These positive results have subsequently been supported by investigations of effects of bisphosphonates on tumour growth in vivo, both in bone and at peripheral sites. A reduction of tumour burden and also in cancer-induced bone disease has been reported following bisphosphonate treatment in several model systems, including breast and prostate cancer, osteosarcoma and multiple myeloma. In addition, bisphosphonates have been shown to significantly reduce growth of human tumour cells (including breast, prostate, lung and mesothelioma) implanted subcutaneously in immunocompromised mice. However, the majority of in vivo studies showing a reduction in bone disease and reduced tumour burden have used high doses and frequent administration of bisphosphonates, and the clinical relevance of these data have therefore been the subject of considerable debate. Bisphosphonates may hold greater promise as anti-tumour agents when used in combination with cytotoxic drugs, and several in vivo studies have reported substantial increased inhibition of tumour growth and improved survival when bisphosphonates have been added to standard chemotherapy regimens. This review will summarise the published data on anti-tumour effects of bisphosphonates from in vivo models, alone and in combination with other anti-cancer agents, and highlight the main lessons learned and future challenges in this field.