The Hippo signaling pathway plays an essential role in adult tissue homeostasis and organ size control. In Drosophila and vertebrates, it consists of a highly conserved kinase cascade, which involve MST and Lats that negatively regulate the activity of downstream transcription coactivators, YAP and TAZ. Through its interaction with TEADs and other transcription factors, they mediate both proliferative and antiapoptotic gene expression and thus regulate tissue repair and regeneration. Dysregulation or mutation of the Hippo pathway is linked to tumorigenesis and cancer development. Recent studies have uncovered multiple upstream inputs, including cell density, mechanical stress, G-protein-coupled receptor (GPCR) signaling, and nutrients, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway as effectors of these biophysical cues and its potential implications in tissue homeostasis and cancer.