Nature Reviews Genetics, Published online: 28 January 2026; doi:10.1038/s41576-025-00929-9De novo gene evolution entails the birth of new genes from previously non-coding DNA. In this Review, Bornberg-Bauer and Eicholt overview how protein-coding de novo genes are identified, the mechanistic and evolutionary processes underlying their emergence and evolution, and the patterns in their encoded protein structures.