Cotton bacterial blight (CBB), an important disease of (Gossypium hirsutum) in the early 20th century, had been controlled by resistance genes for over half a century. Recently, CBB re-emerged as an agronomic problem in the United States. Here, a comparative genomics analysis of host and pathogen was conducted. Phylogenetic analysis revealed that strains from the current outbreak cluster with race 18 Xanthomonas citri pv. malvacearum (Xcm) strains. Type three effector repertoires of 16 Xcm isolates reveal 24 conserved effectors as well as nine variable effectors. In addition, virulent race 18 strains contain 3 to 5 more effectors than non-race 18 strains. Genome assemblies for two geographically and temporally divergent strains of Xcm, yielded circular chromosomes and accompanying plasmids. These genomes encode eight and thirteen distinct transcription activator-like effector genes. RNA-sequencing revealed that both strains induced 52 conserved gene targets in diverse cotton cultivars, including a homeologous pair of genes, with homology to the known susceptibility gene, MLO. In contrast, the two strains of Xcm induced different SWEET sugar transporters and in one case, only one homeolog was significantly induced. Subsequent genome wide analysis revealed the overall expression patterns of the homeologous gene pairs in cotton after inoculation by Xcm. These data reveal host-pathogen specificity in the Xcm-G. hirsutum pathosystem, give explanations for the CBB reemergence, and strategies for future development of resistant cultivars.