The origin and evolution of genes are central themes in evolutionary biology and genomics, shedding light on how molecular innovations shape biological complexity and adaptation. This review explores the principal mechanisms underlying gene emergence in eukaryotes, including gene duplication, de novo gene birth, horizontal gene transfer, viral gene domestication, and exon shuffling. We examine the population dynamics that govern the fixation of new genes, their functional integration, and the selective forces acting upon them-from purifying selection to adaptive innovation. Examples such as and , which originated through recent segmental duplications followed by neofunctionalization, illustrate how duplicate-derived de novo genes can play a key role in human brain development. In addition, we highlight the emerging relevance of nuclear architecture in determining the evolutionary fate of new genes, offering a spatial dimension to gene innovation. We also discuss methodological approaches for detecting new genes and inferring selection, and finally, we highlight the emerging role of the human pangenome in revealing hidden gene diversity and its implications for evolutionary and biomedical research. Understanding gene innovation not only enhances our grasp of evolutionary processes but also informs clinical studies on disease susceptibility and human uniqueness.