The authors present a theoretical model to predict the resonance frequency shift due to molecule adsorption on micro-and nanocantilevers. They calculate the frequency shift experienced by cantilevers made of either silicon or the polymer SU-8, when two adsorbates, myosin protein and an alkanethiol, are attached to the cantilever surface. They demonstrate that the effect of the adsorbate stiffness can be comparable or even larger than the mass effect, producing positive frequency shifts. The results provide methods for decoupling both opposite effects and routes for the design of resonators with high sensitivity to molecule adsorption based on either stiffness or mass effects. © 2006 American Institute of Physics. ͓DOI: 10.1063/1.2388925͔ Microcantilever resonators have been proposed for highly sensitive label-free detection of organic and biological molecules. [1][2][3] The basic principle is the measurement of the resonance frequency shift due to the added mass of the molecules bound to the cantilever surface. The sensitivity is inversely proportional to the active mass of the resonator. Advances in micro-and nanofabrication techniques have motivated an intense effort for scaling the resonator size down in order to push the detection limits. 2,3 Thus the sensitivity of the technique has rapidly evolved from the picogram to the attogram range, by simply reducing the size of the resonators ͑lengthϫ widthϫ thickness͒ from ͑100-500͒ ϫ ͑20-100͒ ϫ ͑0.5-1͒ to ͑5-20͒ ϫ ͑0.5-2͒ ϫ ͑0.1-0.3͒ m 3 . Consequently, the resonance frequency increases from the kilohertz to the megahertz regime. By further reduction of the size to the nanoscale, the detection limits can achieve unprecedented values. 3 Independently of the cantilever size, the quantification of the adsorbed mass is an issue still not resolved. First, when the molecules are not uniformly adsorbed, the resonance frequency critically depends on the distribution of the molecules on the resonator. 4,5 Second, a discrepancy is, in many cases, found between the added mass calculated by the theory and the mass adsorbed on the cantilever. This discrepancy is generally justified by invoking the effect of the adsorption-induced surface stress on the resonance frequency. 6 In this effect, the surface stress is simplified to an external axial force that creates a shearing moment. Recently, Lu et al. 7 have demonstrated that this model is inadequate to describe the physical system because in the real situation, the cantilever free end allows the deformation to relieve the stress. In their theoretical treatment, a strain-dependent surface stress is necessary to observe some effect on the resonant frequency, and therefore the surface stress effect is expected to be negligible in biomolecular applications.Up to date, the influence of the mechanical properties of the adsorbed molecules on the resonance has been neglected. In this work, we present a theoretical model to study the effect of the stiffness of the molecules bound to a microcantilever on the resonance frequency. We demo...