Cells sense mechanical factors in their environment to facilitate critical processes such as adhesion, differentiation, and migration. Accordingly, alteration of cellular forces is an emerging factor in diseases like atherosclerosis and cancer, which makes intuitive sense given that these diseases are often diagnosed by hardened arteries or detecting a lump that feels stiffer than the surrounding tissue. Thus, altered mechanical forces in the microenvironment of cells, or its “mechano-some”, is a potentially targetable and quantifiable factor in disease, much like changes in the genome or proteome. At a molecular level, changes in cell/tissue stiffness that accompany disease reflect alterations in a cell’s tensional homeostasis, where mechanotransduction signaling pathways are aberrantly activated. Decoding the molecular mechanisms utilized by cellular proteins to sense and respond to force has the potential to reveal new “mechano-some” based therapeutic and diagnostic avenues. Our lab uses a combination of structure/function tools such as single molecule spectroscopy, and cellular imaging to elucidate molecular mechanisms used by cell-surface receptors to sense and response to mechanical stimuli.