Metal-organic frameworks (MOFs) have emerged as promising materials for biosensing and biomedical applications due to their exceptional structural properties and tunable functionalities. Integrating functional DNA with MOFs offers numerous advantages, including enhanced colloidal stability, target-induced signal amplification, improved cellular uptake, and controlled drug release. This focused review aims to highlight key insights into the DNA-MOF interface to facilitate the design and application of these conjugates. A succinct summary of the interactions between DNA and MOFs, covering both noncovalent adsorption and covalent conjugation is provided. Moreover, recent advancements in utilizing DNA-MOF conjugates in biosensors, with a specific emphasis on fluorescent and electrochemical sensing are discussed. Additionally, applications in bioimaging, controlled drug delivery, and nucleic acid delivery are explored. Finally, the limitations of existing designs and provide insightful perspectives for the future development of DNA-MOFs, aiming to expedite their integration and impact in the realm of biomedical applications are addressed. Functional nucleic acids can be combined with MOFs to form hybrid materials with unique optical, catalytical, and biological properties. Nucleic acids can adopt various conformations on MOFs, ranging from random adsorption, and precise inclusion, to upright attaching. Understanding and controlling the DNA-MOF interaction enables us to better design smart materials with responsive features under biological settings. image