The widely accepted association between aberrant methylation at specific imprinted loci and distinct imprinting disorders has recently been brought into question by the identification of methylation defects at multiple loci (multilocus methylation defect [MLMD]). Strikingly, in different imprinting disorders, the same MLMD patterns can be observed. The cause for this ambiguous epigenotype-phenotype correlation is currently unknown. Future strategies to solve this enigma have to include all levels of imprinting regulation, ranging from DNA methylation to chromatin organization, as any disturbance of the balanced interaction between the different players in imprinting regulation might cause disturbed expression of imprinted factors. The molecular analysis of MLMD will help in discovering these interactions and contribute to the understanding of genomic imprinting and its disturbances.