The traditional understanding of genetic disease, that, with the exception of aneuploidy, it is due primarily to single base pair changes or small deletions and duplications has been challenged over the last decade. This challenge has been spearheaded by increasing evidence of the frequency and significance of larger genomic rearrangements. It now appears that a substantial proportion of Mendelian conditions are caused by deletions and duplications that involve the copy number of one or more contiguous genes. It is becoming apparent too that de novo chromosomal events are much more frequent than spontaneous point mutations and that chromosomal rearrangement is likely to account for the vast majority of sporadic disease.