Heterosis refers to improved or altered performance observed in F1 hybrid organisms when compared to their parents. Heterosis has revolutionized agriculture by improving key agronomic traits in crop plants. However, even after decades of research in this area a unifying molecular theory of heterosis remains somewhat elusive. For many years the dominant, overdominant, and epistasis models have prevailed for explaining multigenic heterosis. The use of whole transcriptome, proteome, metabolome, and epigenome profiling approaches can further generate and inform hypotheses regarding heterosis. This chapter reviews the models that have been used to explain heterosis. We also review the mechanistic basis of epigenetic pathways in plants and describe how they may also be considered in relation to understanding heterosis. There are number of findings that support potential links between epigenetic regulation and heterosis in model and crop plants, including the potential for DNA methylation, histone modification, and small RNAs to influence heterotic effects in F1 hybrids. Overall, we assess some opportunities and challenges for epigenetic research to advance the molecular understanding of heterosis.