As an alternative to the common disease-common variants hypothesis (Chakravarti 1999; Lander 1996) , the rare variants hypothesis postulates that a collection of many, individually less frequent copy number changes may collectively significantly contribute to disease susceptibility. Although many CNVs are present in an appreciable proportion of the population, the majority are likely to be less frequent: for example, in our array CGH investigation of 50 apparently healthy French male samples, 809 out of 1469 (*55%) multi-probe CNV regions were identified in only one individual (de Smith et al. 2007 ). Rare copy number changes have been implicated in neurodevelopmental disorders, including autism (Marshall et al. 2008; Sebat et al. 2007 ) and schizophrenia (Wilson et al. 2006; Xu et al. 2008 ). Furthermore, a number of rare genomic structural variants have recently been associated with obesity (Bochukova et al. 2010; Walters et al. 2010) , and many more low frequency CNVs with strong effects may contribute to common disease phenotypes: large sample cohorts and different populations will need to be investigated to uncover these rare variants.