The article reviews the advancements in tomato genome sequencing, the impact of human-driven selection, and key genes associated with agronomic traits in tomato breeding. It highlights the potential of genomics-guided breeding and the progress in genome design, including gene editing, de novo domestication, and intelligent breeding. The review also discusses the challenges and future strategies in tomato breeding, emphasizing the importance of sustainable agriculture and evolving human societies. Key topics include the sequencing of reference genomes, pan-genome studies, population genomics, DNA methylation, and the identification of genes controlling important agronomic traits such as flowering time, fruit weight, shape, quality, and disease resistance. The article concludes by discussing the potential of genome design-based breeding and the application of beneficial alleles in improving tomato varieties.The article reviews the advancements in tomato genome sequencing, the impact of human-driven selection, and key genes associated with agronomic traits in tomato breeding. It highlights the potential of genomics-guided breeding and the progress in genome design, including gene editing, de novo domestication, and intelligent breeding. The review also discusses the challenges and future strategies in tomato breeding, emphasizing the importance of sustainable agriculture and evolving human societies. Key topics include the sequencing of reference genomes, pan-genome studies, population genomics, DNA methylation, and the identification of genes controlling important agronomic traits such as flowering time, fruit weight, shape, quality, and disease resistance. The article concludes by discussing the potential of genome design-based breeding and the application of beneficial alleles in improving tomato varieties.