Despite a high abundance and diversity of natural plant pathogens, plant disease susceptibility is rare. In agriculture however, disease epidemics often occur when virulent pathogens successfully overcome immunity of a single genotype grown in monoculture. Disease epidemics are partially controlled by chemical and genetic plant protection, but pathogen populations show a high potential to adapt to new cultivars or chemical control agents. Therefore, new strategies in breeding and biotechnology are required to obtain durable disease resistance. Generating and exploiting a genetic loss of susceptibility is one of the recent strategies. Better understanding of host susceptibility genes (S
) and new breeding technologies now enable the targeted mutation of S
genes for genetic plant protection. Here we summarize biological functions of susceptibility factors and both conventional and DNA nuclease-based technologies for the exploitation of S
genes. We further discuss the potential trade-offs and whether the genetic loss of susceptibility can provide durable disease resistance.
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