Antimicrobial resistance (AMR) is today the greatest medical threat. Despite major efforts in controlling the emergence and spread of AMR bacteria, resistance is world-wide out of control. A major gap in this dilemma, is understanding how and when the genes that determine an optimal combination for a given pathogen are compiled and selected. In order to approach this issue, combination of genomic analysis of wt bacteria from different ecological niches, together with in vitro and in vivo experiments, start to shed light into the complex scenario of gene flow and adaptation of acquired AMR genes and their platforms into novel bacterial hosts. A trade-off between fitness cost and resistance and transmission will ultimately define successful clones. Using these scenario, and in combination with large-scale metagenomics, we have identified gene-plasmid combinations in more than 400 farms in Europe that account for successful AMR clones. Further, we have identified major hotspots for AMR gene flux, and used experimental evolution to assess the basis for plasmid-host adaptation and AMR.