Technical Abstract: The fungal metabolites called aflatoxins are potent naturally occurring carcinogens, produced primarily by Aspergillus flavus and A. parasiticus. A. flavus affects many agricultural crops such as maize, cotton, peanuts, and tree nuts. It can contaminate these crops with aflatoxins in the field before harvest. It is a serious concern because of its toxic and carcinogenic properties and also due to the risk of contamination in food and feed on human health and livestock. It is not only a serious food safety issue, but it has significant economic implications for the agricultural industry worldwide because of restrictions limiting the trade of contaminated crop. Host plant resistance is an effective, efficient and dependable tool to protect crops from the preharvest infection and aflatoxin contamination processes. Host plant resistance to aflatoxin contamination is a complex trait, and dissecting this trait is an equally complex task. With the technological breakthrough in genomics and next-generation sequencing, our understanding on the Aspergillus biology is greatly enhanced. This chapter aggregates the rich aflatoxin literature and focuses on the factors that cause the stress execrably and increase the aflatoxin contamination of grains before and after harvest. Further discussed are potential future prevention technology and strategies that could be employed to guide future research, such as “next-generation” genetics.