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Wheat (Triticum aestivum L.) crop health assumes unprecedented significance in being the second most important staple crop of the world. It is host to an array of fungal pathogens attacking the plant at different developmental stages and accrues various degrees of yield losses owing to these. Tilletia indica that causes Karnal bunt (KB) disease in wheat is one such fungal pathogen of high quarantine importance restricting the free global trade of wheat besides the loss of grain yield as well as quality. With global climate change, the disease appears to be shifting from its traditional areas of occurrence with reports of increased vulnerabilities of new areas across the continents. This KB vulnerability of new geographies is of serious concern because once established, the disease is extremely difficult to eradicate and no known instance of its complete eradication using any management strategy has been reported yet. The host resistance to KB is the most successful as well as preferred strategy for its mitigation and control. However, breeding of KB resistant wheat cultivars has proven to be not so easy, and the low success rate owes to the scarcity of resistance sources, extremely laborious and regulated field screening protocols delaying identification/validation of putative resistance sources, and complex quantitative nature of resistance with multiple genes conferring only partial resistance. Moreover, given a lack of comprehensive understanding of the KB disease epidemiology, host-pathogen interaction, and pathogen evolution. Here, in this review, we attempt to summarize the progress made and efforts underway toward a holistic understanding of the disease itself with a specific focus on the host-pathogen interaction between T. indica and wheat as key elements in the development of resistant germplasm. In this context, we emphasize the tools and techniques being utilized in development of KB resistant germplasm by illuminating upon the genetics concerning the host responses to the KB pathogen including a future course. As such, this article could act as a one stop information primer on this economically important and re-emerging old foe threatening to cause devastating impacts on food security and well-being of communities that rely on wheat.