Many proteins in living cells are subject to mechanical forces, which can be generated internally by molecular machines, or externally, e.g., by pressure gradients. In general, these forces fall in the piconewton range, which is similar in magnitude to forces experienced by a molecule due to thermal fluctuations. While we would naively expect such moderate forces to produce only minimal changes, a wide variety of "mechanosensing" proteins have evolved with functions that are responsive to forces in this regime. The goal of this article is to provide a physical chemistry perspective on protein-based molecular mechanosensing paradigms used in living systems, and how these paradigms can be explored using novel computational methods.