In this Focus Review, nanoarchitectonic approaches for mechanical-action-based chemical and biological sensors are briefly discussed. In particular, recent examples of piezoelectric devices, such as quartz crystal microbalances (QCM and QCM-D) and a membrane-type surface stress sensor (MSS), are introduced. Sensors need well-designed nanostructured sensing materials for the sensitive and selective detection of specific targets. Nanoarchitectonic approaches for sensing materials, such as mesoporous materials, 2D materials, fullerene assemblies, supported lipid bilayers, and layer-by-layer assemblies, are highlighted. Based on these sensing approaches, examples of bioanalytical applications are presented for toxic gas detection, cell membrane interactions, label-free biomolecular assays, anticancer drug evaluation, complement activation-related multiprotein membrane attack complexes, and daily biodiagnosis, which are partially supported by data analysis, such as machine learning and principal component analysis.