Hippo signaling is an evolutionarily conserved network that has a central role in regulating cell proliferation and cell fate to control organ growth and regeneration. It promotes activation of the LATS kinases, which control gene expression by inhibiting the activity of the transcriptional coactivator proteins YAP and TAZ in mammals and Yorkie in Drosophila. Diverse upstream inputs, including both biochemical cues and biomechanical cues, regulate Hippo signaling and enable it to have a key role as a sensor of cells’ physical environment and an integrator of growth control signals. Several components of this pathway localize to cell–cell junctions and contribute to regulation of Hippo signaling by cell polarity, cell contacts, and the cytoskeleton. Downregulation of Hippo signaling promotes uncontrolled cell proliferation, impairs differentiation, and is associated with cancer. We review the current understanding of Hippo signaling and highlight progress in the elucidation of its regulatory mechanisms and biological functions.