Many copy number alterations (CNA) currently interpreted as variants of unknown significance (VUS) will ultimately be determined to be benign; however, their classification requires a more extensive characterization of the human genome than currently exists. There is no definitive set of rules or level of evidence required to define a CNA as benign. The information needed to accurately assess the pathogenic impact of CNA is beginning to be assembled. Although the lack of understanding of the human genome can make clinical array-comparative genomic hybridization interpretation frustrating, it is precisely why clinical human genetics is an exciting arena in which to work.