Heterosis (or hybrid vigor) refers to a natural phenomenon whereby hybrid offspring of genetically diverse individuals out-perform their parents in multiple traits including yield, adaptability and resistances to biotic and abiotic stressors. Innovations in technology and research continue to clarify the mechanisms underlying crop heterosis, however the intrinsic relationship between the biological basis of heterosis remain unclear. In this review, we aim to provide insight into the molecular genetic basis of heterosis by presenting recent advances in the 'omics' of heterosis and the role of non-coding regions, particularly in relation to energy-use efficiency. We propose that future research should focus on integrating the expanding datasets from different species and hybrid combinations, to mine key heterotic genes and unravel interactive 'omics' networks associated with heterosis. Improved understanding of heterosis and the biological basis for its manipulation in agriculture should help to streamline its use in enhancing crop productivity.