Summary Transmembrane adhesion proteins play an important role in molecular transport, signal transduction, energy utilization and many other basic cellular functions. Their activity is modulated by mechanical signals, that are typically sensed and transduced through changes in conformation, function and biochemical interactions. Integrin transmembrane receptors respond to mechanical forces from the microenvironment by changing conformation and ligand binding. These changes regulate the assembly of adhesions between cells and the extracellular environment and, in turn, control cell activity, including spreading and migration. However, the molecular origin of these mechanisms remains largely elusive. The present research is focused on determining the molecular origin of integrin mechanosensing and how it relates to cell motion using multiscale modeling techniques. We will combine molecular dynamics simulations with new coarse-graining methods and mesoscale stochastic approaches in order to identify the conformational pathways underlying the responses of integrin to variations in the mechanics of the microenvironment. Then, we will study how this conformational pathway regulates cell motion. Results will reveal the molecular mechanisms underlying mechanochemical functions of integrin, for future control of cells’ activity in several human pathologies.