Melioidosis is a neglected tropical disease caused by the environmental bacterium Burkholderia pseudomallei, estimated to cause 165,000 infections and 89,000 deaths annually worldwide. In endemic regions such as northeast Thailand, healthy individuals show serological evidence of exposure from early childhood, yet only a small proportion develop symptomatic disease. We hypothesise that genetic factors in both the human host and B. pseudomallei influence this transition from exposure to infection. Since 2019, we have established a cohort to collect and characterise the genomes of melioidosis patients and healthy individuals living in the same endemic area who have never developed the disease, along with B. pseudomallei isolates from both clinical infections and household environments. Pangenome analysis shows that B. pseudomallei possesses an extensive pangenome, likely maintained by adaptation to variable environmental conditions. This diversity promotes the persistence of genotypes that, while not universally optimal, confer fitness advantages in specific contexts such as infection. Pangenome-based genome-wide association studies have identified bacterial alleles linked to infection, including some overlapping with vaccine targets currently under development. On the host side, pangenome analysis enables the detection of population-specific genetic variants. Unlike the genetically diverse bacterium, the studied human population exhibits signatures of inbreeding, which may increase the frequency of certain recessive alleles and contribute to higher susceptibility to B. pseudomallei infection. Collectively, integrating host and pathogen pangenome analyses provides a useful framework to uncover the genetic determinants of susceptibility, offering opportunities for targeted prevention and intervention against melioidosis.