A previous study (Nat. Genet. 42, 203–209, 2010) suggested a 'two-hit' model for the severity of developmental delay in individuals with a microdeletion at chromosome 16p12.1. Now, Evan Eichler and colleagues expand the two-hit model to a broader genomic context (N. Engl. J. Med. 367, 1321–1331, 2012). They performed array–comparative genomic hybridization (aCGH) analysis of 32,587 children with developmental delay. As a control set, they analyzed 8,329 individuals who did not display overt neurological disorders. They identified 2,312 children with developmental delay who carried 1 of 72 rare copy-number variants (CNVs), most of which have been associated with intellectual disability. Of the 2,312 children, 200 also harbored an additional large autosomal CNV. The authors observed an enrichment of second-site hits in children with a phenotypically variable genomic disorder, supporting the hypothesis that additional genetic variants contribute to phenotypic variation. Information on the mode of inheritance was available for 46 children with first- and second-site CNVs, which indicated that 33 of 46 of the second-site variants were inherited. Finally, the authors analyzed detailed clinical data for 161 children (96 with a first-site variant and 65 with multiple variants) and found a qualitative increase in deficits in those with multiple variants.