Many fastidious (or unculturable) pathogens, such as the Candidatus Liberibacter spp. associated with citrus greening (HLB) disease pose an immense threat to crop production and cause billions of dollars in losses worldwide. Unlike studies of model plant-pathogen systems, studies of fastidious crop pathogens are greatly hindered due to the unculturable, obligate lifestyle of the pathogens and the relative recalcitrance of the host crops to conventional genetic and laboratory evaluation approaches. To overcome these bottlenecks, we developed an innovative plant hairy root-based efficacy testing system suitable for faster pre-screening of diverse resistance and susceptibility genes and small molecule-based antimicrobials. Using this approach, we identified multiple novel genes, antimicrobial peptides, and chemicals that showed efficacy against Candidatus Liberibacter spp. Ongoing field trials with selected candidates are promising, with improved crop yield and health. One or more of these solutions could be further deployed as products for crop disease management.