Our research program has established genetic and epigenetic mechanisms by which polyploidy and hybridization reshape gene expression and phenotype, providing a mechanistic framework for understanding genome evolution and hybrid vigor in plants. We use omics and systems biology approaches, along with genetic, cellular, and molecular biology methodologies, to address these fundamental biological questions using Arabidopsis (a weedy plant in the mustard family), corn or maize (a hybrid crop), and cotton (a polyploid crop) as experimental systems. Our research findings elucidated that epigenetic mechanisms regulate nucleolar dominance and genome-wide nonadditive gene expression in plant hybrids and polyploids, contributing to both hybrid vigor (heterosis) and inbreeding depression. These regulatory and transcriptional changes influence circadian rhythms associated with heterosis, energy and metabolic networks underlying inbreeding depression, and phenotypic variation, including enhanced stress responses, increased seed size via small RNA-mediated pathway, and improved fiber cell development, during polyploid evolution and plant domestication. Our team also led international efforts to sequence and analyze the genomes and epigenomes of all five allotetraploid cotton species, as well as the pan-genomes of 113 wild and cultivated accessions of Upland and Pima cotton. These landmark resources have substantially advanced cotton improvement and provided a foundation for studying polyploid genome evolution and function. A distinctive contribution of our work has been to integrating polyploidy and heterosis with epigenetics and gene expression into a unified framework for elucidating plant genome evolution and crop performance. Importantly, research findings on plant hybrid genetics, epigenetics, and polyploidy have broader relevance to sexually reproducing organisms, including humans. Hybrid vigor and inbreeding depression, for example, are widespread across animals. Likewise, because many cancer cells exhibit polyploidy and aneuploidy, understanding how polyploid plants regulate and balance gene dosage may provide new insights and strategies for cancer research, with potential implications for human health.