Perceived by Charles Darwin in many vegetable plants and rediscovered by George H Shull and Edward M East in maize, heterosis or hybrid vigour is one of the most widely utilized phenomena, not only in agriculture but also in animal breeding. Although, numerous studies have been carried out to understand its genetic and/or molecular basis in the past 100 years, our knowledge of the underlying molecular processes that results in hybrid vigour can best be defined as superficial. Even after century long deliberations, there is no consensus on the relative/individual contribution of the genetic/epigenetic factors in the manifestation of heterosis. However, with the recent advancements in functional genomics, transcriptomics, proteomics, and metabolomics-related technologies, the riddle of heterosis is being reinvestigated by adopting systems-level approaches to understand the underlying molecular mechanisms. A number of intriguing hypotheses are converging towards the idea of a cumulative positive effect of the differential expression of a variety of genes, on one or several yield-affecting metabolic pathways or overall energy-use efficiency, as the underlying mechanism for the manifestation of heterosis. Presented here is a brief account of clues gathered from various investigative approaches targeted towards better scientific understanding of this process.