Epigenetic mechanisms may actually initiate or drive disease processes, rather than present as historical markers of previous pathological events. Mendelian disorders that manifest as epigenetic diseases may arise through inheriting mutations in genes encoding DNA and chromatin modifiers as well as nucleosomal and architectural proteins. Because these proteins have pleiotropic effects on the expression of several genes, their mutation can result in complex phenotypes, masking their causal Mendelian origins. In contrast to Mendelian epigenetic diseases, epimutations such as aberrant DNA methylation can result in congenital non-Mendelian diseases such as genomic imprinting disorders. Acquired genetic mutations as well as epimutations can drive late onset diseases such as cancer. This review will examine the balance between genetic and epigenetic interactions, highlighting examples of congenital diseases caused through Mendelian and non-Mendelian transmission. Therapeutic epigenetic intervention strategies are increasingly being developed and we now have the potential for reversing even developmentally-induced mental retardation, by normalising epigenetically controlled gene expression.