Cantilevers immersed in liquid experience viscous damping and hydrodynamic loading. We report on the use of such cantilevers, operating in the dynamic mode with, (i) frequency sweeping and (ii) phase locked loop methods. The solution to reliability issues such as random drift in the resonant peak values, and interference of spurious modes in the resonance frequency spectrum, are explained based on the actuation signal provided and laser spot size. The laser beam spot size and its position on the cantilever were found to have an important role, on the output signal and resonance frequency. We describe a method to distinguish the normal modes from the spurious modes for a cantilever. Uncertainties in the measurements define the lower limit of mass detection (m min). The minimum detection limits of the two measurement methods are investigated by measuring salt adsorption from phosphate buffer solution, as an example, a mass of 14 pg was measured using the 14th transverse mode of a m × 100 μm × 1 μm silicon cantilever. The optimized measurement was used to study the interaction between antibody and antigen. © 2016 IOP Publishing Ltd.