Cells sense changes in external mechanical forces or the environment. This mechanosensation is relayed to the interior of the cell through actin cytoskeleton and myosin contractility, which results in mechanotransduction of physical forces into biochemical information. Whereas the importance of mechanotransduction in development and diseases is widely acknowledged, the early signalling steps of mechanosensation towards actin and myosin are poorly understood. In this Research Article, Sean Sun and colleagues (He et al., 2018) mechanically compress cells by means of a microfluidic device to monitor the early events in mechanosensation. They find that membrane tension-sensitive cation channels and Ca2+ currents are important messengers for detecting tension changes. These changes lead to an active regulation of the small GTPase Rho and, consequently, cortical myosin contraction to balance the external forces. Moreover, the inhibition of Ca2+ or blocking a cation channel decreases the change in Rho activity after mechanical compression. Interestingly, the authors show that the tension-sensitive transcription factor Yes-associated protein (YAP) translocates from the nucleus to the cytoplasm following this compression. They conclude with a mechanochemical model to explain the key features of mechanosensation. This article sheds light on the early steps of the response of a cell to external mechanical forces.