Epigenetic silencing of genes that are important for DNA repair, cell cycle control, apoptosis, and cellular interactions with the extracellular matrix has been causally linked to several subtypes of cancer. Translating this knowledge of the implications of promoter methylation to wide and routine use in clinical pathology laboratories has been more challenging than the case of genetic analyses because epigenetic modifications do not change the underlying sequence of the affected nucleic acid, rendering polymerase chain reaction analysis alone uninformative. Two epigenotyping assays that detect promoter methylation are currently standard of care in treatment of two distinct tumor types in only a few top hospitals across the United States. Both rely on a harsh chemical step that degrades over 90% of tumor DNA samples, which are often available in limited quantities, and imparts the potential for false-negative or false-positive results if the reaction conditions are not exactly correct. Using nanotechnology and biotechnology to devise practical new analysis techniques that avoid the drawbacks of current techniques represents a powerful approach that is likely to significantly increase the clinical use of this class of biomarkers in the coming years. WIREs Nanomed Nanobiotechnol 2017, 9:e1407. doi: 10.1002/wnan.1407 For further resources related to this article, please visit the WIREs website.