Abstract: Asian-cultivated rice (Oryza sativa L.) consists of two subspecies, indica (Oryza sativa L. indica) and japonica (Oryza sativa L. japonica) subspecies. There are considerable differences between them in morphology, physiology and gene level. The stronger heterosis generated by the genetic differences between inter-subspecies could improve the yield potential of rice. However, the application of heterosis in indica-japonica subspecies is limited because of the serious hybrid sterility in F₁ hybrid. Hybrid sterility, a common form of postzygotic reproductive isolation, is universal and complex, controlled by multiple hybrid sterility loci. The discovery of wide-compatible varieties (WCVs) provides the possibility to overcome interspecific hybrid sterility as the F₁ hybrids show normal fertility whether WCVs crossed with indica or japonica rice. In this paper, we summarize the indica-japonica divergence, the genetic basis of hybrid sterility in indica-japonica subspecies, the identified hybrid sterility QTL and genes, and analyze the molecular mechanisms of the cloned hybrid sterility genes and the function of wide-compatible genes. On this basis, we propose four approaches to overcome inter-subspecific hybrid sterility, and improve the fertility of indica-japonica F₁ hybrids precisely, including breeding inter-subspecific introgression rice, developing indica-compatible japonica lines and wide-compatible lines, and creating wide-compatible genes by gene editing technology. The application of indica-japonica hybrid rice will promote a major change in rice industry.