Despite advances in the investigation of nanoscopic mechanobiology and the development of macroscale mechanotransduction, methods capable of operating at the microscale remain limited. This Review describes the physical principles and engineering of microscale droplets, including liquid constructs and hydrated polymer (hydrogel) beads, which are emerging as versatile biointerfaces for mechanical measurement and mechanotransduction in living matter. The microscale compositions and mechanical properties of droplets recapitulate key aspects of cellular mechanical responses, enabling non-invasive mechanical detection. Furthermore, droplets can contain stimulus-responsive materials that enable the transduction of mechanical cues into diverse biochemical or bioelectrical outputs. Applications of microscale droplets include cellular force and viscoelasticity sensors deployed in intercellular or intracellular environments, as well as synthetic carriers for controlled drug release and the modulation of biological activities.