The review starts with a general outlook of the main mechanisms of action of antimicrobial proteins and peptides, with the final aim of understanding the biological function of antimicrobial RNases, and identifying the key events that account for their selective properties. Although most antibacterial proteins and peptides do display a wide-range spectrum of action, with a cytotoxic activity against bacteria, fungi, eukaryotic parasites and viruses, we have only focused on their bactericidal activity. We start with a detailed description of the main distinctive structural features of the bacteria target and on the polypeptides, which act as selective host defence weapons.Following, we include an overview of all the current available information on the mammalian RNases which display an antimicrobial activity. There is a wealth of information on the structural, catalytic mechanism and evolutionary relationships of the RNase A superfamily. The bovine pancreatic RNase A (RNase A), the reference member of the mammalian RNase family, has been the main research object of several Nobel laureates in the 60s, 70s and 80s. A potential antimicrobial function was only recently suggested for several members of this family. In fact, the recent evolutionary studies indicate that this protein family may have started off with a host defence function. Antimicrobial RNases constitute an interesting example of proteins involved in the mammalian innate immune defence system. Besides, there is wealth of available information on the mechanism of action of short antimicrobial peptides, but little is known on larger polypeptides, that is, on proteins. Therefore, the identification of the mechanisms of action of antimicrobial RNases would contribute to the understanding of the proteins involved in the innate immunity.