Sarcomas are mesenchymal cancers, which, in many cases, have distinctive molecular features. Limb-sparing surgery delivered at specialised sarcoma centres as part of a multidisciplinary approach has become the standard treatment for most patients and usually provides excellent local control. Preoperative treatment with chemotherapy is most common for patients with bone sarcomas. The ideal sequence of surgery and radiation for local management of soft-tissue sarcoma remains controversial on the basis of early versus late treatment complications, although preoperative radiation can provide the best results for improved long-term function. New methods for radiation delivery and tumour sensitisation might provide further improvements. However, metastatic disease is common, and conventional chemotherapy provides for only a narrow therapeutic window outside of a few responsive pathological subtypes. Targeting underlying molecular events in specific sarcomas can provide for dramatic benefits, as has been seen with imatinib treatment for gastrointestinal stromal tumours and dermatofibrosarcoma protuberans. Trials of agents targeting the cell cycle and angiogenesis in soft-tissue sarcomas, and of those targeting osteoclasts in bone sarcomas, are currently underway. Biological data and preclinical studies support trials using inhibitors of hedgehog signalling in chondrosarcoma, inhibitors of wnt/β-catenin in osteosarcoma and aggressive fibromatosis, and inhibitors of histone deacetylases in synovial sarcoma and Ewing sarcoma. Pharmacogenetic approaches will be needed to identify individual determinants of response and outcome in order to maximise the benefits of targeting specific molecular events and keep side-effects to a minimum. Research in stem-cell biology and nanotechnology holds promise for additional novel treatment options in the future.