The three p53 family members, p53, p63 and p73, are structurally similar and 
share many biochemical activities. Yet, along with their common fundamental role 
in protecting genomic fidelity, each has acquired distinct functions related to 
diverse cell autonomous and non-autonomous processes. Similar to the p53 family, 
the Hippo signaling pathway impacts a multitude of cellular processes, spanning 
from cell cycle and metabolism to development and tumor suppression. The core 
Hippo module consists of the tumor-suppressive MST-LATS kinases and oncogenic 
transcriptional co-effectors YAP and TAZ. A wealth of accumulated data suggests 
a complex and delicate regulatory network connecting the p53 and Hippo pathways, 
in a highly context-specific manner. This generates multiple layers of 
interaction, ranging from interdependent and collaborative signaling to apparent 
antagonistic activity. Furthermore, genetic and epigenetic alterations can 
disrupt this homeostatic network, paving the way to genomic instability and 
cancer. This strengthens the need to better understand the nuances that control 
the molecular function of each component and the cross-talk between the 
different components. Here, we review interactions between the p53 and Hippo 
pathways within a subset of physiological contexts, focusing on normal stem 
cells and development, as well as regulation of apoptosis, senescence and 
metabolism in transformed cells.