It is currently well established that multicellular organisms live in tight association with complex communities of microorganisms including a large number of bacteria. These are immersed in complex interaction networks reflecting the relationships established between them and with host organisms; yet, little is known about the molecules and mechanisms involved in these mutual interactions. Ribosomally synthesized peptides, among which bacterial antimicrobial peptides called bacteriocins and microcins have been identified as contributing to host–microbe interplays, are either unmodified or post-translationally modified peptides. This review will unveil current knowledge on these ribosomal peptide-based natural products, their interplay with the host immune system, and their roles in microbial interactions and symbioses. It will include their major structural characteristics and post-translational modifications, the main rules of their maturation pathways, and the principal ecological functions they ensure (communication, signalization, competition), especially in symbiosis, taking select examples in various organisms. Finally, we address unanswered questions and provide a framework for deciphering big issues inspiring future directions in the field.