**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** FUSARIUM WILT CAUSED BY FUSARIUM OXYSPORUM F. SP. VASINFECTUM RACE 4 (FOV4) IS ONE OF THE MAJOR PROBLEMS AFFECTING COTTON PRODUCTION WORLDWIDE. FOV4 IS HIGHLY VIRULENT ON SUSCEPTIBLE COTTON ENTRIES AND IT PERSISTS IN THE FIELD FOR YEARS AS NO TREATMENT IS KNOWN TO ELIMINATE IT FROM THE SOIL. CURRENTLY, BREEDING UPLAND (G. HIRSUTUM) AND PIMA (G. BARBADENSE) RESISTANT CULTIVARS IS THE PRIMARY METHOD OF FOV4 CONTROL. SINCE SOUTHERN ROOT KNOT NEMATODE (RKN) INFESTATION MAKES COTTON MORE SUSCEPTIBLE TO FOVS, INCLUDING FOV4, IT IS IMPERATIVE TO STUDY COTTON RESPONSE TO BOTH PATHOGENS. THE MOLECULAR MECHANISMS BEHIND THE RESISTANCE RESPONSES TO FOV4 AND RKN IN COTTON ARE STILL POORLY UNDERSTOOD, HINDERING THE SYSTEMATIC DEVELOPMENT OF RESISTANT COTTON CULTIVARS. OUR PRELIMINARY RESULTS ON GENE EXPRESSION ANALYSIS OF RESISTANT/SUSCEPTIBLE COTTON ENTRIES INFECTED WITH FOV4 AND/OR RKN, SUGGESTS THE PARTICIPATION OF SPECIFIC RECEPTORS AND TRANSCRIPTION FACTORS THAT COULD REPRESENT DETERMINANTS OF THE RESISTANCE RESPONSE. THIS PROJECT AIMS AT GAINING INSIGHTS OF THE PRINCIPLES OF COTTON DEFENSE MECHANISMS TO BOTH PATHOGENS AND IDENTIFY CANDIDATE GENES USEFUL FOR GERMPLASM IMPROVEMENT. WE WILL TAKE ADVANTAGE OF THE PROGRESS TO DATE THROUGH CONVENTIONAL BREEDING FOR INTROGRESSING GENES FOR RESISTANCE TO FOV4 (AND ALSO TO FOV1 AND RKN), THE POWER OF RNA-SEQUENCING AND ASSOCIATED BIOINFORMATIC ANALYSES TO STUDY THE MOLECULAR MECHANISMS CONTROLLING COTTON RESPONSES TO FOV4 AND RKN INFECTION. IMPLEMENTING THE MOST MODERN TECHNIQUES, THE POTENTIAL OF THESE CANDIDATE GENES TO CONFER RKN AND FOV4 RESISTANCE WILL BE EVALUATED IN NON-RESISTANT COTTON ENTRIES. THE RESULTS OF THIS STUDY WILL POSITIVELY IMPACT FOV4/RKN BREEDING STRATEGIES AND PROVIDE KNOWLEDGE TO DESIGN MORE EFFECTIVE CONTROL SCHEMES USEFUL TO COTTON PRODUCERS.