The establishment of gap junctional intercellular communication is a prerequisite for appropriate control of tissue homeostasis. Gap junctions consist of connexin proteins, whereby a myriad of factors govern the connexin life cycle. At the transcriptional level, most attention has yet been paid to the classical cis/trans machinery (i.e. the interaction between transcription factors and regulatory elements in connexin gene promoter regions) as a gatekeeper of connexin expression. In the last few years, it has become clear that epigenetic processes are also essentially involved in connexin gene transcription. Major determinants of the epigenome include histone modifications and DNA methylation, and recently, microRNA species have also been described as key regulators of the epigenetic machinery. In the present paper, the emerging roles of epigenetic events in the control of connexin expression, and consequently of gap junctional intercellular communication, are reviewed. Besides an updated theoretical background concerning gap junctions and epigenetic phenomena, we provide an in-depth overview of their interrelationship and we demonstrate the clinical relevance of the topic.