Body tissues and organs are exposed to a variety of stresses throughout their lifespan. It is known that some tissues can rapidly induce protective mechanisms in response to injury, but if and how this protection, termed ‘cytoprotection’, functions during normal development or physiology remains unclear. Now, Helen Weavers and colleagues report that Drosophila renal tissues rely on balanced cytoprotection to drive both developmental and homeostatic stress resilience. They first reveal that the cytoprotective factors Nrf2 and Gadd45 are expressed within the energetically and biosynthetically active ‘principal’ cells of Drosophila renal tubules. They further show that the spatial and temporal pattern of Nrf2 activity correlates with that of renal tubule metabolic and physiological activity. The researchers also demonstrate that RNAi-mediated loss of Nrf2 from post-embryonic tubules causes disturbed tubule morphology, increased oxidative damage and osmoregulatory defects. Likewise, RNAi-mediated knockdown of Gadd45 results in defective tubule morphogenesis associated with increased DNA damage and apoptosis. Finally, the authors report that, while renal Nrf2 activity and Gadd45 expression increase in response to exogenous stress, the constitutive overexpression of Gadd45 or Nrf2 does not confer additional benefits but rather has a negative impact on tubule morphology and function in the absence of stress. Together, these findings suggest that cryoprotective factors and mechanisms must be precisely regulated to support renal tubule development and physiology.