In contrast, a number of bacteria are naturally resistant against some antibiotics. The molecular basis for natural resistance may be a general factor like the lack of the targeted pathway, a variant of the targeted molecule that is not inhibited by the antibiotic or a membrane limiting entry of the antibiotic into the cell. In addition natural resistance may also be mediated by a resistance gene belonging to the cell’s core genes. Such resistance genes are vertically inherited, shared by (nearly) all isolates of a species and co-evolve with their hosts. They are often encoded by the chromosome, are usually immobile and their expression level is tightly regulated or very low. The establishment of such a resistance requires a long lasting, usually mild selection pressure as it may be present in the soil, which contains many microorganisms producing antibiotics. Examples for this type of natural resistance are the chromosomally encoded β-lactamases found in several species of the Enterobacteriaceae (Naas et al., 2008), many of them colonising plants and soil.