The ability of legumes to acquire sufficient nitrogen from the symbiosis with Rhizobium relies on the intimate contact between the endosymbiotic, intracellular rhizobia, called bacteroids, and their host cells, the symbiotic nodule cells. Nodules contain several thousand symbiotic cells, each harboring thousands of bacteroids. Bacteroids are differentiated bacteria which have a specific metabolism and in many legumes their formation is accompanied with a morphological transformation involving strong cell enlargement and genome amplification. We have shown that in Medicago and related legumes, the symbiotic nodule cells produce large amounts of highly diverse nodule-specific effector peptides, called NCRs. NCRs control the bacteroid differentiation by inducing their elongation and DNA amplification. The NCR peptides are similar to antimicrobial peptides (AMPs) of innate immunity in animals and plants and can kill rhizobia in vitro. The BacA protein of Sinorhizobium meliloti provides protection against the antimicrobial activity of NCRs and other AMPs with similar mode of action and intracellular rhizobia require the BacA protein to survive the challenge of the NCR peptides in the nodule cells. BacA is conserved among many bacteria and several animal pathogens also require BacA or BacA-like proteins for pathogenesis and chronic infection of their host, most likely by providing protection against host produced innate immunity AMPs. BacA and BacA-like proteins belong to the ABC transporter family. However, what is transported and how this protein provides protection against AMPs remain unknown. Several hypotheses are discussed.