Electrochemical DNA sensors offer high sensitivity, selectivity, and low cost for detecting specific DNA sequences or mutated genes associated with human diseases. These sensors exploit nanoscale interactions between the target DNA, recognition layer, and solid electrode surface. Various electrochemical detection methods have been developed, including direct electrochemistry of DNA, electrochemistry at polymer-modified electrodes, electrochemistry of DNA-specific redox reporters, electrochemical amplifications with nanoparticles, and electrochemical devices based on DNA-mediated charge transport chemistry. Over the past 15 years, significant technological advancements have been made, enabling the development of new techniques for monitoring biorecognition and interaction events on solid devices and in solution. 'Gene chips' featuring dense arrays of oligonucleotides have been successfully applied to transcriptional profiling and single-nucleotide polymorphism (SNP) discovery, but their fluorescence-based readout requires sophisticated instrumentation and numerical algorithms, limiting their use to research laboratories. Recently, innovative designs for DNA-based electrochemical sensing have emerged, combining nucleic acid layers with electrochemical transducers to create simple, accurate, and inexpensive platforms for patient diagnosis. These sensors promise to provide sensitive multiplexed assays for clinical diagnostics of genetic and infectious diseases. The review includes illustrative examples and compares different design platforms, discussing their potential for clinical and point-of-care applications. The principles of biosensor function rely on specific recognition events to detect target analytes. Molecular-based biosensors typically include a molecular recognition layer and a signal transducer coupled to a readout device. DNA is well-suited for biosensing due to its specific and robust base-pairing interactions. The minimal elements of a biosensor include a molecular recognition layer and a signal transducer, with the signal transduction method determining the readout technology (optical, mechanical, or electrochemical). Optical readouts, such as fluorescence and surface plasmon resonance (SPR), offer high sensitivity but require sophisticated instrumentation. Electrochemical readouts, which provide an electronic signal directly, are well-suited for DNA diagnostics due to their simplicity, low cost, and portability. Electrochemical methods can be further enhanced through electrochemical amplification techniques, such as those involving nanoparticles, to improve detection limits and sensitivity. The review also discusses the application of DNA-based sensors to detect proteins and small molecules bound to DNA, highlighting the potential for high-throughput protein screening and the development of sensitive environmental sensors. Despite the challenges in fabricating large arrays and handling biological complexity, the authors conclude that electrochemical DNA sensors offer significant promise for clinical and diagnostic applications.Electrochemical DNA sensors offer high sensitivity, selectivity, and low cost for detecting specific DNA sequences or mutated genes associated with human diseases. These sensors exploit nanoscale interactions between the target DNA, recognition layer, and solid electrode surface. Various electrochemical detection methods have been developed, including direct electrochemistry of DNA, electrochemistry at polymer-modified electrodes, electrochemistry of DNA-specific redox reporters, electrochemical amplifications with nanoparticles, and electrochemical devices based on DNA-mediated charge transport chemistry. Over the past 15 years, significant technological advancements have been made, enabling the development of new techniques for monitoring biorecognition and interaction events on solid devices and in solution. 'Gene chips' featuring dense arrays of oligonucleotides have been successfully applied to transcriptional profiling and single-nucleotide polymorphism (SNP) discovery, but their fluorescence-based readout requires sophisticated instrumentation and numerical algorithms, limiting their use to research laboratories. Recently, innovative designs for DNA-based electrochemical sensing have emerged, combining nucleic acid layers with electrochemical transducers to create simple, accurate, and inexpensive platforms for patient diagnosis. These sensors promise to provide sensitive multiplexed assays for clinical diagnostics of genetic and infectious diseases. The review includes illustrative examples and compares different design platforms, discussing their potential for clinical and point-of-care applications. The principles of biosensor function rely on specific recognition events to detect target analytes. Molecular-based biosensors typically include a molecular recognition layer and a signal transducer coupled to a readout device. DNA is well-suited for biosensing due to its specific and robust base-pairing interactions. The minimal elements of a biosensor include a molecular recognition layer and a signal transducer, with the signal transduction method determining the readout technology (optical, mechanical, or electrochemical). Optical readouts, such as fluorescence and surface plasmon resonance (SPR), offer high sensitivity but require sophisticated instrumentation. Electrochemical readouts, which provide an electronic signal directly, are well-suited for DNA diagnostics due to their simplicity, low cost, and portability. Electrochemical methods can be further enhanced through electrochemical amplification techniques, such as those involving nanoparticles, to improve detection limits and sensitivity. The review also discusses the application of DNA-based sensors to detect proteins and small molecules bound to DNA, highlighting the potential for high-throughput protein screening and the development of sensitive environmental sensors. Despite the challenges in fabricating large arrays and handling biological complexity, the authors conclude that electrochemical DNA sensors offer significant promise for clinical and diagnostic applications.