Our epigenome is characterized by its ability to dynamically respond to intra- and extracellular stimuli. These epigenetic changes are reversible and consequently are potential contributors to health and disease. Epigenetic biomarkers are emerging as tools for the screening and early detection of various diseases, for prognostic and treatment monitoring, and for predicting future risk of disease development. In clinical practice, this will contribute to the development of in vitro diagnostic and prognostic tools, which in turn may also lead to advances in personalized medicine. In this chapter we propose a definition for epigenetic biomarkers and describe different technologies used for their discovery and analysis. Furthermore, we focus our attention on issues and obstacles that need to be solved before adopting them into clinical routine. Finally, we present a perspective on the implantation of epigenetic biomarkers in clinical laboratories and their use in clinical diagnostics.