Introduction: Analysis of circulating tumor DNA is a promising approach to guide the treatment of cancer patients but despite large efforts it has not been broadly applied in the clinic. Technical obstacles and lack of standardization have hampered the process and it has proved challenging to make highly sensitive analyses available for all patients. Research has focused on the use of somatic mutations but because of large mutational diversity among patients the setup becomes unmanageable for daily routine use. Areas covered: Methylations are key events in cancer development and can be used as markers for the presence of circulating tumor DNA similar to how mutations have been used. This review focuses on analytical aspects and possible clinical applications of methylated ctDNA in plasma from cancer patients. Expert commentary: Technical and clinical challenges of mutation and methylation analyses are similar. However, the possibility to analyze a limited number of methylations present in all tumors of a certain type allows for proper validation and standardization of the analyses. Tumor-specific methylation analyses could supplement or substitute mutation analyses for certain clinical applications and assist the progress of the clinical use of circulating tumor DNA.