The dominant and sometimes competing theories for the aetiology of complex human disease have been the common disease, common variant (CDCV) hypothesis, and the multiple rare variant (MRV) hypothesis. With the advent of genome wide association studies and of second-generation sequencing, we are fortunate in being able to test these ideas. The results to date suggest that these hypotheses are not mutually exclusive. Further, initial evidence suggests that both MRV and CDCV can be true at the same loci, and that other disease-related genetic mechanisms also exist at some of these loci. We propose calling these, pleomorphic risk loci, and discuss here how such loci not only offer understanding of the genetic basis of disease, but also provide mechanistic biological insight into disease processes.