Mechanical biosensors are essential for detecting biological interactions at the molecular and cellular levels. They offer unique advantages in measuring forces, displacements, and mass changes. This review discusses micro- and nanoscale biosensors, focusing on fast mechanical biosensing in fluid using mass- and force-based methods. Challenges include non-specific interactions and the need for improved device performance, fabrication reproducibility, and system integration. Advances in micro- and nanofabrication enable the development of mechanical devices with nanosized moving parts, allowing practical biosensors that can be mass-produced. Mechanical biosensors capitalize on advantageous scaling properties. Nanoscale sensors provide high mass resolution, with NEMS achieving zeptogram-scale resolution in vacuum and nanogram resolution in fluid. Mechanical compliance increases with size reduction, converting force into measurable displacement. Small fluidic devices can respond quickly, enabling observation of biological processes on millisecond timescales. Mechanical biosensors are categorized into four types based on chemical interactions: affinity-based, fingerprint, separation-based, and spectrometric assays. Surface-stress sensors measure deflection caused by biomolecules binding to functional groups. Dynamic-mode sensors oscillate with resonance frequency, changing when molecules bind. These sensors can monitor bacterial growth in humid environments or detect biomarkers in fluid. They offer high sensitivity and fast response times, but viscous damping in fluid reduces mass resolution compared to gas or vacuum. Dynamic-mode mass sensing has been used for individual cell mass measurements. However, viscous damping in fluid reduces sensitivity. Suspended microchannel resonators (SMRs) offer high Q values but have modest performance due to non-specific binding. They have been used to detect glycoprotein ALCAM in serum and measure cell mass and density during yeast cell cycles. Other mechanical biosensors include quartz crystal microbalances (QCM), whispering-gallery microcavity resonators, optical microring resonators, and nanowire biosensors. QCMs measure mass changes in vacuum, gas, or fluid. Whispering-gallery microcavity resonators offer high sensitivity but face challenges in reproducibility. Optical microring resonators provide label-free detection but have lower sensitivity. Nanowire biosensors detect changes in conductance when target molecules bind, offering femtomolar to picomolar sensitivity. Sensitivity is critical for detecting rare biomarkers in blood plasma. Current sensors can detect PSA at 4 ng/ml, but better diagnostics are needed. Non-specific binding poses a fundamental noise floor, limiting detection. Strategies to overcome this include label-free detection, sandwich assays, and signal amplification techniques. PCR and enzyme-linked immunosorbent assays (ELISA) offer high sensitivity but are not suitable for all applications. Diffusion, convection, and reaction kinetics influence sensor performance. For microfluidic devices, critical length and time to reach steady-state depend on binding affinity and flow geometry. Depletion in bulk solution can affect sensitivity, especially in small sample volumes. Force and energyMechanical biosensors are essential for detecting biological interactions at the molecular and cellular levels. They offer unique advantages in measuring forces, displacements, and mass changes. This review discusses micro- and nanoscale biosensors, focusing on fast mechanical biosensing in fluid using mass- and force-based methods. Challenges include non-specific interactions and the need for improved device performance, fabrication reproducibility, and system integration. Advances in micro- and nanofabrication enable the development of mechanical devices with nanosized moving parts, allowing practical biosensors that can be mass-produced. Mechanical biosensors capitalize on advantageous scaling properties. Nanoscale sensors provide high mass resolution, with NEMS achieving zeptogram-scale resolution in vacuum and nanogram resolution in fluid. Mechanical compliance increases with size reduction, converting force into measurable displacement. Small fluidic devices can respond quickly, enabling observation of biological processes on millisecond timescales. Mechanical biosensors are categorized into four types based on chemical interactions: affinity-based, fingerprint, separation-based, and spectrometric assays. Surface-stress sensors measure deflection caused by biomolecules binding to functional groups. Dynamic-mode sensors oscillate with resonance frequency, changing when molecules bind. These sensors can monitor bacterial growth in humid environments or detect biomarkers in fluid. They offer high sensitivity and fast response times, but viscous damping in fluid reduces mass resolution compared to gas or vacuum. Dynamic-mode mass sensing has been used for individual cell mass measurements. However, viscous damping in fluid reduces sensitivity. Suspended microchannel resonators (SMRs) offer high Q values but have modest performance due to non-specific binding. They have been used to detect glycoprotein ALCAM in serum and measure cell mass and density during yeast cell cycles. Other mechanical biosensors include quartz crystal microbalances (QCM), whispering-gallery microcavity resonators, optical microring resonators, and nanowire biosensors. QCMs measure mass changes in vacuum, gas, or fluid. Whispering-gallery microcavity resonators offer high sensitivity but face challenges in reproducibility. Optical microring resonators provide label-free detection but have lower sensitivity. Nanowire biosensors detect changes in conductance when target molecules bind, offering femtomolar to picomolar sensitivity. Sensitivity is critical for detecting rare biomarkers in blood plasma. Current sensors can detect PSA at 4 ng/ml, but better diagnostics are needed. Non-specific binding poses a fundamental noise floor, limiting detection. Strategies to overcome this include label-free detection, sandwich assays, and signal amplification techniques. PCR and enzyme-linked immunosorbent assays (ELISA) offer high sensitivity but are not suitable for all applications. Diffusion, convection, and reaction kinetics influence sensor performance. For microfluidic devices, critical length and time to reach steady-state depend on binding affinity and flow geometry. Depletion in bulk solution can affect sensitivity, especially in small sample volumes. Force and energy