Since the publication of the classical studies of the Dutch scientist J.D. van der Waals in 1873, physical scientists have known that many—if not most—properties of matter can be rationalized by the strength and direction of the forces that molecules exert on each other. Even strictly macroscopic phenomena, such as the elasticity and the melting points of solids, the viscosity and boiling points of liquids, or the compressibility of gases, are macroscopic manifestations of the myriad of small interactions between molecules, and of the forces that molecules exert on one another. Moreover, in 1889, Svante Arrhenius proposed that reactions between molecular species follow pathways that involve the formation of some type of strained, largely unstable, high-energy transition state whose accessibility along the reaction coordinate controls the rate of the reaction. Since then, chemists have recognized that chemical affinity results from the attractive interactions between chemical entities and that stresses and strains often develop within and between these entities in the course of chemical reactions. Until very recently, chemists and biochemists have had to rely on bulk methods to investigate the properties of molecules and their reactions. These methods did not make it possible to directly investigate the nature, strength, and direction of intermolecular forces and torques. During the last few years, however, the advent of novel methods of single-molecule manipulation have begun to offer researchers, for the first time, the opportunity to measure directly the forces holding molecular structures together, to measure the stresses and strains generated in the course of chemical and biochemical reactions, to exert external forces to alter the fate of these reactions, and to reveal the rules that govern the interconversion of mechanical and chemical energy in these reactions. This area of research can be rightly called mechanochemistry. Biochemical processes as diverse as protein folding, DNA elasticity, the protein-induced bending of DNA, the stress-induced catalysis of enzymes, the mechanical properties of protein motors, and even the ubiquitous process of induced-fit molecular recognition of proteins for their ligands, are all examples in which stresses and strains develop in molecules as they move along a reaction coordinate. In 1992, we published the results of the first experiments in which a single DNA molecule was mechanically manipulated and stretched to determine its bending and extensional properties (Smith et al. 1992). This work was the basis of a number of assays of DNA-dependent protein machines and laid the experimental and conceptual groundwork for studies of enzyme mechanism at the single molecule level. In what follows, I describe some of the recent and ongoing projects currently being carried out in our laboratory using these novel methods.