limitations of such interfacial systems, it is important to understand the mechanisms involved in systems where biological components are interfaced with graphene.Graphene has been investigated as a robust and sensitive platform for biosensing, both through field-effect transistor (FET) biosensors and electrochemical biosensors. [16][17][18][19] FET biosensors can offer a sensitive detection platform that is able to detect very low concentrations (≈fg mL −1 ) of pathogens with a near-instantaneous response. [20] On the other hand, electrochemical biosensors enable the detection of target pathogens with little to no additional sample preparation, as well as in situ detections. [21] However, FET biosensors typically involve complicated photolithography and deposition processes for device fabrication. Electronic flow through electrochemical biosensors can interfere with the target analyte and/or trigger unwanted electrochemical reactions on the sensor's surface. To this end, Raman spectroscopy provides a versatile bioanalytical platform to assess label-free, chemically, and spatially defined information of cells and tissues at the molecular level. [22][23][24] Although Raman spectroscopy is not the only vibrational spectroscopy used for biomedical analysis, it offers numerous advantages compared to other spectroscopic techniques, such as 1) the ability to analyze aqueous samples, since water has a small Raman cross-section, [25,26] whereas it has high absorbance in Fourier transform infrared (FTIR) resulting in possible interference with the sample's spectrum; 2) the ability to scan over a wide range of wavenumbers with high spatial resolution; 3) label-free analysis, as the fundamentals underlying Raman spectroscopy enable the study of tissues/cells in their native states. The molecule-specific bands in Raman spectra provide direct information about the biochemical composition.Numerous review articles are available documenting the interaction of graphene and biological systems [14,15,[27][28][29][30] as well as understanding the behavior of biosystems using Raman spectroscopy. [22][23][24]31] However, probing the graphene biointerface with Raman spectroscopy by analyzing the phononic changes in graphene, rather than the biological signatures, offers unique advantages as graphene phonons are shown to be sensitive to the interfacial events that accompany carrier doping. [32] The objective of this review is to delineate the principles and mechanisms involved in the sensitive graphene phononic modification resulting from the interface with different biosystems and to evaluate the potential biomedical field applications (Figure 1).Leveraging the phononic sensitivity and scalability of nano-biointerfaces has accelerated the growth of unique and versatile biosensors. Graphene has the properties of a near-ideal signal transducer, due to the strong coupling between its interfacial and phononic properties. This enables sensitive yet quick detection of surface interactions on graphene via Raman spectral analysis. The Raman-ac...