The understanding of polyploidy and hybrid vigor is among the grand challenges in evolution and plant biology and vital to agriculture, food production, renewable energy, and the environment. Moreover, polyploidy provides a means to permanently fix the heterozygosity and hybrid vigor in interspecific hybrids. Using Arabidopsis and maize as model systems, we have employed genomic, molecular biology, and systems biology approaches to investigate genetic and epigenetic mechanisms for gene expression changes and phenotypic variation in allopolyploids and hybrids. We found a direct link between epigenetic regulation of circadian clock to the adaptation of strains to local environments. Further, ploidy regulation of small RNAs controls gene expression in endosperm and seed size. These mechanistic insights into polyploidy and hybrid vigor will ultimately help us improve the production of plant hybrids and allopolyploids to meet the growing demands for food, feed, fiber, and biomaterials.