Nucleic acids epigenetic modifications including DNA and RNA methylation and post transcriptional gene regulation by noncoding RNAs (ncRNAs) such as microRNAs and long ncRNAs (lncRNAs), are of great relevance due to their role in mammalian development and the initiation and progression of various diseases like cancer. Over the past decades, a great research effort was made for determining nucleic acid methylation, electrochemical biosensors rapidly developing as efficient analytical tools for the determination of epigenetic modification of nucleic acids. In this review article, a critical overview of recently reported advances in their development and use for the determination of epigenetic modifications of nucleic acids, including the presence of methylated bases in DNA and RNA and the aberrant expression of microRNAs and lncRNAs, is provided. Special emphasis is made on methodologies successfully applied to real clinical samples, unmet challenges or key points toward future research.