© 2016 Elsevier Inc. All rights reserved. Clinical epigenetics research is a rapidly expanding field that investigates the contribution of epigenetic systems to human health and disease. Increasing numbers of clinical researchers are entering this exciting field and are searching for ways to include epigenetics in their work. Here, we review commonly used techniques to assay epigenetic marks, including methods to examine deoxyribonucleic acid modifications, histone modifications, chromatin structure, and noncoding ribonucleic acids. We profile classic methods going back to the 1970s as well as recently developed methods relying on next-generation sequencing technologies, highlighting their advantages and limitations. We review challenges specific to clinical epigenetics research and discuss how new methods development might overcome remaining obstacles.