Polyploidy is widespread and particularly common in angiosperms. The prevalence of polyploidy in the plant suggests it as a crucial driver of diversification and speciation. The paleopolyploid soybean (Glycine max) is one of the most important crops of plant protein and oil for humans and livestock. Soybean experienced two rounds of whole genome duplication around 13 and 59 million years ago. Due to the relatively slow process of post-polyploid diploidization, most genes are present in multiple copies across the soybean genome. Growing evidence suggests that polyploidization and diploidization could cause rapid and dramatic changes in genomic structure and epigenetic modifications, including gene loss, transposon amplification, and reorganization of chromatin architecture. This review is focused on recent progresses about genetic and epigenetic changes during polyploidization and diploidization of soybean and represents the challenges and potentials for application of polyploidy in soybean breeding.