Polyploidy or whole genome duplication (WGD) occurs throughout the evolutionary history of many plants and some animals, including crops such as wheat, cotton, and sugarcane. Recent studies have documented rapid and dynamic changes in genomic structure and gene expression in plant polyploids, which reflects genomic and functional plasticity of duplicate genes and genomes in plants. Common features of uniparental gene regulation and nonadditive gene expression in regulatory pathways responsive to growth, development, and stresses in many polyploids have led to the conclusion that epigenetic mechanisms including chromatin modifications and small RNAs play central roles in shaping molecular and phenotypic novelty that may be selected and domesticated in many polyploid plants and crops.