Functional graphene nanomaterials (FGNs) are fast emerging materials with extremely unique physical and chemical properties and physiological ability to interfere and/or interact with bioorganisms; as a result, FGNs present manifold possibilities for diverse biological applications. Beyond their use in drug/gene delivery, phototherapy, and bioimaging, recent studies have revealed that FGNs can significantly promote interfacial biointeractions, in particular, with proteins, mammalian cells/stem cells, and microbials. FGNs can adsorb and concentrate nutrition factors including proteins from physiological media. This accelerates the formation of extracellular matrix, which eventually promotes cell colonization by providing a more beneficial microenvironment for cell adhesion and growth. Furthermore, FGNs can also interact with cocultured cells by physical or chemical stimulation, which significantly mediate their cellular signaling and biological performance. In this review, we elucidate FGNs-bioorganism interactions and summarize recent advancements on designing FGN-based two-dimensional and three-dimensional architectures as multifunctional biological platforms. We have also discussed the representative biological applications regarding these FGN-based bioactive architectures. Furthermore, the future perspectives and emerging challenges will also be highlighted. Due to the lack of comprehensive reviews in this emerging field, this review may catch great interest and inspire many new opportunities across a broad range of disciplines.