Emerging 2D van der Waals compounds have gained increasing attention due to their unique electronic and optical properties, and have shown promise in sensing applications. The realization of sensing devices using these materials still faces several challenges. For example, it is critical to gain clear understandings of (1) the fundamental light-matter interactions and their relations to the atomic structures, which govern many key material properties and device performances; and (2) the coupling with other nanostructures and molecules, which is a required structure for sensing devices and systems. This talk introduces new discoveries and pioneering works on these critical challenges, and novel applications of these materials in biochemical sensing. The first part of this talk presents light-matter interactions and techniques to augment material performance, such as 2D Janus transition metal dichalcogenides. The second part of this talk focuses on the interaction of 2D materials with organic molecules and related sensing applications. In particular, a novel enhancement effect of molecular Raman signals on 2D surface was discovered, which offers a new paradigm of biochemical sensing with high specificity, high multiplexity, and low noise. The selection rule for the 2D material substrates has been revealed, which is critical for device design. Two sensing applications for Alzheimer’s disease and respiratory viruses will also be discussed. Overall, the works presented in this talk are significant in fundamental quantum science, and offer important guidelines for practical applications in sensing and quantum technologies. The methodologies used here also provide a framework for the future study of many emerging materials and sensing scenarios.