We have developed an innovative research program to study molecular mechanisms for gene regulation and evolutionary variation in plant hybrids (formed between strains of the same or different species) and allopolyploids (formed between two or more related species) compared to their parents. Our research employs Arabidopsis (a weedy plant in the mustard family), cron (a hybrid crop), and cotton (a polyploid crop) as experimental systems and uses genomic, proteomic, and systems biology approaches, as well as genetic and cell and molecular biology methodologies. Our research findings established that epigenetic mechanisms including  small RNAs and DNA methylation 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, and improved fiber cell development, during polyploid evolution and plant domestication. Our team also led an international effort 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 integrate 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.