Normally folded prion protein is abundant in the CNS and remarkably conserved, suggesting that it has important functions, yet these functions have remained elusive. Now the work of Parrie et al. has codified a requirement for prion protein in adult neurogenesis. Their insightful use of prion protein knockout and over-expressing mice, combined with the well-characterized olfactory system site of neurogenesis, demonstrated that prion protein promotes proliferation and survival of adult neurons. The work provides a unique independent confirmation of prion protein playing a role in neuroprotection, especially extending the conclusion beyond models using acute injury. Parrie et al. (2018) further show that prion protein is required for CNS axon guidance. A growing list of phenotypes associated with prion protein loss are coincident with symptoms of neurodegenerative disease and dementia, though it remains contentious whether any such disruption of prion protein function contributes to disease aetiology. Perhaps most intriguingly, identifying the developmental functions for prion protein opens new avenues to understand the evolution of prion protein: what history led to a CNS protein that is conserved and abundant paradoxically being both dispensable for life and the template for devastating disease?