Lipid II-degrading M-class bacteriocins are protein antibiotics that kill a narrow spectrum of bacterial strains through cleavage of lipid II, thereby leading to an arrest of cell wall synthesis and cell lysis. A number of M-class bacteriocins have been structurally and functionally characterized, which include colicin M from Escherichia coli, syringacin M from Pseudomonas syringae, and pyocin M (PaeM) from P. aeruginosa. In each case, these bacteriocins have been shown to kill bacteria closely related to the producing strain, with selectivity mediated through the presence of a specific outer membrane receptor. Cell killing requires uptake of the bacteriocin into the periplasm where it is able to cleave lipid II in a metal-dependent manner. Calcium and magnesium have been shown to support enzymatic activity, and X-ray crystal structures of syringacin M and PaeM, respectively, show these ions bound at the putative active site. Extensive structural and mutagenesis studies have enabled delineation of the functional domains of the M-class bacteriocins that mediate receptor binding, translocation across the outer membrane, and cytotoxic activity.