X-linked hypophosphataemia is the most frequent cause of familial rickets resistant to treatment with physiological amounts of vitamin D [1-3]. It is also one of the great mysteries of metabolic bone disease, since so little is known about phosphate regulation. However in the past decade research on phosphate transport in this disorder has been considerably illuminated by studies on the hypophosphataemic animal homologue, the Hyp mouse, whose mutant locus is at the distal end of the X chromosome [4]. Since not all physicians hold the mouse in high regard theclinical relevance of this work may have been undervalued; but recent discoveries now bring hypophosphataemic man and mouse together and provide a fascinating metabolic story. Not only has the human X-linked hypophosphataemic gene been localized [5-7] but another murine hypophosphataemic gene (called Gy) has been described, in which both hearing and the vestibular apparatus are defective [8]. What is the significance of these findings? What further lessons can be learnt from the mouse? And where should we go from here? Inherited hypophosphataemia, and the rickets it usually causes, differs from all other forms of rickets, from acquired hypophosphataemia (often associated with specific tumours [9]), and also from phosphate depletion, as with excessive oral aluminium hydroxide [10]. Growth failure, widespread calcification of the tendons and ligaments [2, 11] which may lead to spinal stenosis and paraplegia [12] and absence of proximal myopathy, possibly related to normal intramyofibrillar inorganic phosphate concentration [13], distinguish X-linked hypophosphataemia. Although in this disease disturbances of parathyroid hormone and vitamin D metabolism have been sought, and sometimes found [14], this experiment of Nature certainly appears to be a primary disorder of phosphate transport and as such has the potential to teach us a lot about phosphate metabolism. Important steps have been taken to identify the gene causing X-linked hypophosphataemia using the techniques of modern molecular biology. Multilocus linkage analysis was performed using a series of cloned X-chromosome genetic markers in 16 informative hypophosphataemic families from Britain, Canada and America [5, 7, 15]. These families had at least three generations in whom individuals were affected in a pattern consistent with X-linked dominant inheritance. The mutant locus was mapped to the short arm of the human X chromosome and its position could be related to the Hyp locus in the mouse by a scheme involving rearrangement of homologous blocks of genes [5]. This was the first dominant disease gene to be mapped to the