The areas of research considered in this chapter were not directly included in the Cambridge population-based study. However, these studies are important in that they further identified some of the possible pathophysiological mechanisms that underpin the physical and behavioural characteristics that the diagnostic criteria have identified as being central to the syndrome. For example, the very striking features of obesity, short stature and impaired sexual development, together with the less obvious features of temperature dysregulation, abnormal pain threshold and abnormal body composition, all require an explanation. In essence, it is important to establish whether these apparently diverse abnormalities might be traced back to a common single causal mechanism (and by implication the absence of expression of one gene) and, if so, whether the fundamental biological deficits consequent upon the PWS genotype are central (i.e. an abnormality of brain function) or more peripheral and due to abnormal feedback mechanisms, for example, from the gut and/or fat stores. An alternative view is that PWS should be seen as a ‘contiguous gene disorder’ and that it is the absence of expression of more than one imprinted gene that leads to the full PWS phenotype. If more than one gene is involved, then there may not be a single unifying pathophysiology, but rather, different and discrete pathological mechanisms that lead to particular phenotypic abnormalities.