Abstract: Stress signaling following axon injury stimulates a transcriptional program for regeneration that might be exploited to promote central nervous system repair. However, this stress response drives neuronal apoptosis in non-regenerative environments. This duality presents a quandary for the development of therapeutic interventions: manipulating stress signaling to enhance recovery of damaged neurons risks accelerating neurodegeneration or restricting regenerative potential. This dichotomy is well illustrated by the fates of retinal ganglion cells (RGCs) following optic nerve crush. In this central nervous system injury model, disruption of a stress-activated MAP kinase (MAPK) cascade blocks the extensive apoptosis of RGCs that occurs in wild-type mice (Watkins et al., 2013; Welsbie et al., 2017). However, targeting that pathway also limits the efficacy of interventions, such as knockout of the tumor suppressor PTEN, that allow for modest RGC axon regeneration (Watkins et al., 2013). Blocking a parallel injury-response pathway, the integrated stress response (ISR), partially protects injured RGCs, but its contribution to transcription and axon regeneration has, until recently, remained obscure (Yang et al., 2016; Larhammar et al., 2017). Our investigations have revealed that this “secondary” arm plays an unexpectedly comprehensive role in the injury response, controlling not only neurodegeneration but also axon regenerative potential (Somasundaram et al., 2023). These findings suggest that the coordinated action of these parallel stress pathways is required for both repair and apoptosis, underscoring the need for greater understanding of the additional mechanisms that determine which of these outcomes prevails.