Heterosis has historically been exploited in plants; however, its underlying genetic mechanisms and molecular basis remain elusive. In recent years, due to advances in molecular biotechnology at the genome, transcriptome, proteome, and epigenome levels, the study of heterosis in vegetables has made significant progress. Here, we present an extensive literature review on the genetic and epigenetic regulation of heterosis in vegetables. We summarize six hypotheses to explain the mechanism by which genes regulate heterosis, improve upon a possible model of heterosis that is triggered by epigenetics, and analyze previous studies on quantitative trait locus effects and gene actions related to heterosis based on analyses of differential gene expression in vegetables. We also discuss the contributions of yield-related traits, including flower, fruit, and plant architecture traits, during heterosis development in vegetables (e.g., cabbage, cucumber, and tomato). More importantly, we propose a comprehensive breeding strategy based on heterosis studies in vegetables and crop plants. The description of the strategy details how to obtain F1 hybrids that exhibit heterosis based on heterosis prediction, how to obtain elite lines based on molecular biotechnology, and how to maintain heterosis by diploid seed breeding and the selection of hybrid simulation lines that are suitable for heterosis research and utilization in vegetables. Finally, we briefly provide suggestions and perspectives on the role of heterosis in the future of vegetable breeding.