The history of diphosphonates began with studies of inorganic pyrophosphate. This compound was found to occur in many biological fluids and inhibited the precipitation of calcium phosphates. It also slowed the transformation of amorphous calcium phosphate to its crystalline form, and inhibited crystal aggregation and dissolution. These observations suggested that it might be a compound of physiological or pathophysiological significance, perhaps in hypophosphatasia and in renal lithiasis. Diphosphonates are compounds where the P-O-P bond of pyrophosphate is replaced by a P-C-P bond. Many diphosphonates have been synthesized and tested and some relationship of their structure to the spectrum of biological effects has been observed. These analogues have similar properties to pyrophosphate, but unlike pyrophosphate they are resistant to enzymic degradation. Their experimental properties have led to their clinical development as bone scanning agents and in the treatment of disorders of ectopic mineralization and increased bone resorption.