The development of biosensors has seen recent growth owing to their wide range of potential applications from the defending of bioterrorism to the detection of various diseases. Recent investigations in highly sensitive nanomaterials containing nanotechnology suggest the possibility of its advanced applications as biosensors in different biomedical fields. Besides highlighting the characteristic features of different classes of advanced biosensor across different fields of potential application, this article gives a clear overview of some specific investigations related to the surface immobilizations of piezoelectric biosensors employing effective materials and advanced technologies. Further, the current development of piezoelectric biosensors in the detection of potential biomolecules for advanced biomedical applications is critically reviewed. The qualitative and quantitative sensitivity of piezoelectric biosensors, various expressions of resonant frequency shift with changes in mass, thickness, density, and stress for piezoelectric materials are distinctly explored. The importance of several novel nanomaterials for the detection of various diseased biomolecules is clearly illustrated. This study concludes that proper selection of materials is potential to bring improvement in quality as well as reduction in cost of advanced biosensor devices.