In using the frequency domain as a unified platform for representing topology of the sample and capabilities of an instrument, it is shown that instrument transfer functions, when applied to scanned probe instruments such as the atomic force microscope, serve as a powerful design and analysis tool. An instrument transfer function approach is proposed to capture the characteristics of atomic force microscopes (AFM) for sample surface metrology applications. Two practical case studies for metrology of micro and nanomanufacturing areas of research are presented. First, we examined the problem of merging multiple data sets for metrology of polymer-based microfluidic devices. A methodology for the design of registration markers for data alignment is proposed using a spatial frequency-domain framework to determine parameters such as fiducial marker size and pitch. Second, accurate interpretation of atomic force microscope data in micro and nanochannel measurements in biological applications is presented.