Remarkable developments in understanding the physiology and pathophysiology of bone have led to new treatments. RANKL was identified as a key mediator of osteoclast development and function in vitro and in vivo. RANKL expression was observed in a species of benign bone tumor, giant cell tumour of bone (GCTB). The use of denosumab, a fully monoclonal antibody to human RANKL, to treat unresectable, locally advanced or metastatic GTCB was first reported in 2010. Since then, confirmatory studies have indicated that denosumab provides long-term disease control for a subset of patients with few other options. There has been interest in the use of denosumab as an adjuvant to curative surgery, with unclear results to date. More recently another benign connective tissue tumor, tenosynovial giant cell tumour (TGCT), has been targeted with agents blocking CSF-1 signalling, with promising results. TGCT is characterised by a translocation involving CSF-1 and the COl6A3 gene, resulting in dependence on CSF-1 signalling. These studies point to an important emerging theme in oncology—the use of targeted therapies to treat benign neoplasms. Here I will discuss important implications for clinical trials design, not previously encountered in oncology. These include defining meaningful outcomes, whether there is a role for adjuvant therapy, and the long-term complications of blocking important signalling pathways.