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The recent Society for Molecular Biology and Evolution Satellite Meeting on De Novo Gene Birth, hosted at Texas A&M University on November 6-9, 2023, represented the first-ever opportunity for scientists studying the evolution and biology of de novo genes to gather through a dedicated meeting and discuss about groundbreaking discoveries in this emerging and exciting field of gene evolution. In this perspective, we discuss recent advances and major open questions in de novo gene emergence and evolution that were presented at the SMBE satellite meeting, as well as some of the key recent findings published before or since the conference. These key themes include de novo gene identification, function and evolution, what we are learning about de novo genes from experimental analyses of random peptides, de novo gene birth and microproteins, and the role of de novo genes in human disease.