Mechanical testing of micro- and nanoscale materials is challenging due to the intricate nature of specimen preparation and handling and the required load and displacement resolution. In addition, in Situ testing requires the entire experimental setup to be drastically miniaturized, because conventional high-resolution microscopes or analytical tools usually have very small chambers. These challenges are increasingly being addressed using microelectromechanical systems (MEMS)-based sensors and actuators. Because of their very small size, MEMS-based experimental setups are the natural choice for materials characterization under virtually all forms of in Situ electron, optical, and probe microscopy. The unique advantage of such in Situ studies is the simultaneous acquisition of qualitative (up to near atomic visualization of microstructures and deformation mechanisms) and quantitative (load, displacement, flaw size) information of fundamental materials behavior. In this article, we provide a state-of-the-art overview of design and fabrication of MEMS-based devices for nanomechanical testing. We also provide a few case studies on thin films, nanowires, and nanotubes, as well as adhesion-friction testing with a focus on in Situ microscopy. We conclude that MEMS devices offer superior choices in handling, actuation, and force and displacement resolutions. Particularly, their tight tolerances and small footprints are difficult to match by off-the-shelf techniques.