The pathogenesis of cancer hypercalcaemia is an enigma that continues to challenge clinical investigators. Several possible mediators and pathways seem to be operating. To date, humoral and cellular mediators have been found to arise in tumour or normal tissues. The pathophysiological pathways that lead to osteolysis and hypercalcaemia are in large part determined by the biology of the specific tumour. Thus, the mechanisms that give rise to osteolysis in a metastatic breast cancer may be distinct from those that are operating in a non-metastatic lung carcinoma. The morbid consequences of excessive osteolysis and hypercalcaemia are usually similar and require prompt attention. Current research holds out the promise of identifying the agents and pathways responsible for cancer hypercalcaemia. Therapies may one day exist which arrest the specific pathophysiological processes which are operating.