At the linear DNA level, gene activity is believed to be driven by binding of transcription factors, which subsequently recruit the RNA polymerase to the gene promoter region. However, it has become clear that transcriptional activation involves large complexes of many different proteins, which not only directly recruit components of the transcription machinery but also affect the DNA folding. Such proteins, including various chromatin-modifying enzymes, alter among other processes nucleosome positioning and histone modifications and are potentially involved in changing the overall structure of the chromatin and/or the position of chromatin in the nucleus. These epigenetic regulatory features are now known to control and regulate gene expression, although the molecular mechanisms still need to be clarified in more detail. Several diseases are characterized by aberrant gene-expression patterns. Many of these diseases are linked to dysregulation of epigenetic gene-regulatory systems. To interfere with aberrant gene expression, a novel approach is emerging as a disease therapy, involving engineered transcription factors. Engineered transcription factors are based on, for example, zinc-finger proteins (ZFP) that bind DNA in a sequence-specific manner. Engineered transcription factors based on ZFP are fused to effector domains that function to normalize disrupted gene-expression levels. Zinc-finger proteins most likely also influence epigenetic regulatory systems, such as the complex set of chemical histone and DNA modifications, which control chromatin compaction and nuclear organization. In this chapter, we review how epigenetic regulation systems acting at various levels of packaging the genome in the cell nucleus add to gene-expression control at the DNA level. Since an increasing number of diseases are described to have a clear link to epigenetic dysregulation, we here highlight 10 examples of such diseases. In the second part, we describe the different effector domains that have been fused to ZFPs and are capable of activating or silencing endogenous genes, and we illustrate how these effector domains influence epigenetic control mechanisms. Finally, we speculate how accumulating knowledge about epigenetics can be exploited to make such zinc-finger-transcription factors (ZF-TF) even more effective.