Fusarium head blight (FHB), or scab, for its devastating nature to wheat production and food security, has attracted worldwide attention. Multidisciplinary efforts have been made to fight against FHB for a long time, but the great progress has been achieved only in the genomics era of the past 20 years. We have made a long-term effort on investigating the mechanism underlying the excellent FHB resistance showing in the Chinese indigenous cultivar Wangshuibai. We found that this line carries multiple QTL for FHB resistance. A map-based cloning approach was applied to isolate the major QTL, Fhb1 and Fhb5. Fhb1 results from a rare deletion involving the 3′ exon of the histidine-rich calcium-binding-protein gene on chromosome 3BS. Lines of different genetic backgrounds transformed with the Fhb1 resistance allele constantly showed better resistance. A few EMS-induced Fhb1 mutants were obtained and some of them became susceptible. Transcriptional profile changes were evident in the mutant lines. Using a similar approach, we determined the Fhb5 candidate that was confirmed through genetic complementation. We found that pyramiding of the Wangshuibai FHB resistance QTL in elite lines from different wheat-growing areas substantially elevated FHB resistance.