The bisphosphonate clodronate has been widely used in the treatment of hypercalcaemia and osteolytic bone metastases. It can normalize plasma calcium in most hypercalcaemic, rehydrated cancer patients when increased bone resorption is the prevailing disturbance of calcium metabolism. When given intravenously either as a single infusion or as repeated daily administrations, serum calcium levels fall to normal 3-5 days after the onset of therapy. Long-term maintenance treatment must be adjusted individually since relapse appears to depend upon the tumour type, the degree of malignancy and any anticancer therapy. In patients in whom increased tubular calcium reabsorption is the prevailing disturbance of calcium metabolism, the effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be reproduced experimentally in bisphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from various tumour types including lung, kidney, breast and neuroendocrine tumour of the pancreas. In patients having a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3. This homeostatic response probably explains why hypocalcaemia occurs rarely in clodronate-treated patients. No serious side-effects of treatment have been reported. Clodronate appears to be a safe and effective treatment for the hypercalcaemia of malignancy, where increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium.