Our understanding of the causes of mental retardation is benefiting greatly from whole-genome scans to detect submicroscopic pathogenic copy number variants (CNVs) that are undetectable by conventional cytogenetic analysis. The current method of choice for performing whole-genome scans for CNVs is array genomic hybridization (AGH). Several platforms are available for AGH, each with its own strengths and limitations. This review discusses considerations that are relevant to the clinical use of whole-genome AGH platforms for the diagnosis of pathogenic CNVs in children with mental retardation. Whole-genome AGH studies are a maturing technology, but their high diagnostic utility assures their increasing use in clinical genetics.