We have developed a strategy to distinguish between the methylation patterns of homologous chromosomes in tissues, and to follow these patterns in human pedigrees. This genetic approach uncovered evidence of variation in the methylation of allelic sites on homologous chromosomes. This variation was tissue-specific and reproducible after transmission through the germ line, demonstrating that homologous chromosomes have distinct blueprints for the tissue-specific regulation of methylation. Furthermore, this approach can be used to study the relationship between parental imprinting and methylation in native mammalian loci.