Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae were detected shortly after the introduction of broad spectrum cephalosporins in hospitals. Today, they are prevalent in the community, in animals, foods, and the environment. Many factors contribute to the broad distribution, especially the usage of antimicrobials in humans and animals, and due to multiple resistances, not only the usage of beta-lactams and cephalosporins. This broad distribution of ESBLs cannot be fully explained by clonal spread of successful strains. Horizontal transmission of resistance genes, located on transmissible elements, probably plays a much greater role. This gene transfer also enables new combinations of resistance genes which causes therapeutic problems. The complex interactions make it difficult to estimate the relative contribution of the different sources. Resistance genes are broadly distributed in humans, animals, and the environment and the distribution pattern seems to become more similar. It is also evident that two major transmission pathways have to be considered, human-to-human transmission, frequently in hospitals and the exchange of resistance genes between humans, animals, food, and the environment. For the latter, the transfer can go in both directions. Further studies are necessary to understand the pathways between the different reservoirs, the bacterial concentration needed, and the factors having an impact on colonization and transmission. Multiple measures on both the human and veterinary side have to complement each other and interact. A One Health approach needs to be developed and rigorously established.