Mechanical strain regulates the development, organization, and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. Here, we showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then beta-catenin. Inhibition of Yap1- and beta-catenin-mediated transcription blocked cell cycle reentry and progression through G(1) into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion, and beta-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Thus, activation of Yap1 and beta-catenin may represent a master regulator of mechanical strain-induced cell proliferation, and cadherins provide signaling centers required for cellular responses to externally applied force.