Phenotypically discordant monozygotic twins offer the possibility of gene discovery through delineation of molecular abnormalities in one member of the twin pair. One proposed mechanism of discordance is postzygotically occurring genomic alterations resulting from mitotic recombination and other somatic changes. Detection of altered genomic fragments can reveal candidate gene loci that can be verified through additional analyses. We investigated this hypothesis using array comparative genomic hybridization; the 50K and 250K Affymetrix GeneChip® SNP arrays and an Illumina custom array consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events and small aberrations beyond the detection level of our experimental approach cannot be ruled out. The stability of genomes we observed in our study samples also suggests that detection of discordant events in other monozygotic twin pairs would be remarkable and of potential disease significance.