The development of mature B and T cells in the lymphoid system involves a series of molecular decisions that culminate in the expression of a single antigen receptor on the cell surface, a phenomenon termed allelic exclusion. While feedback inhibition of the recombinase-activation gene proteins evidently plays an important role in the maintenance of allelic exclusion, the initial restriction of rearrangement to only one allele in each cell seems to be achieved through monoallelic epigenetic changes. Epigenetic mechanisms involved in the establishment of allelic exclusion also play a central role in other types of monoallelic expression, including X-chromosome inactivation in female cells, and parental imprinting. In all three systems, the inequality of the two alleles seems to be achieved mainly by differential DNA methylation, asynchronous DNA replication, differential chromatin modifications, unequal nuclear localization, and non-coding RNA. In this review, we discuss the unifying features among these monoallelically expressed systems and the unique characteristics displayed by each of them.