The potato genome, sequenced using a homozygous doubled-monoploid clone, reveals 39,031 protein-coding genes and evidence for at least two genome duplication events, indicating a paleopolyploid origin. The potato genome is the first of an asterid, a large angiosperm clade, and contains 2,642 genes specific to this clade. Gene family expansion, tissue-specific expression, and recruitment of genes to new pathways contributed to the evolution of tuber development. The high heterozygosity and inbreeding depression in potato were explored, revealing frequent gene presence/absence variants and other potentially deleterious mutations. The potato genome sequence provides a platform for genetic improvement of this vital crop.The potato genome, sequenced using a homozygous doubled-monoploid clone, reveals 39,031 protein-coding genes and evidence for at least two genome duplication events, indicating a paleopolyploid origin. The potato genome is the first of an asterid, a large angiosperm clade, and contains 2,642 genes specific to this clade. Gene family expansion, tissue-specific expression, and recruitment of genes to new pathways contributed to the evolution of tuber development. The high heterozygosity and inbreeding depression in potato were explored, revealing frequent gene presence/absence variants and other potentially deleterious mutations. The potato genome sequence provides a platform for genetic improvement of this vital crop.