Lipid II is an essential cell-wall precursor required for the growth and replication of both Gram-positive and Gram-negative bacteria. Compounds that use lipid II to selectively target bacterial cells for destruction represent an important class of antibiotics. Clinically, vancomycin is the most important example of an antibiotic that operates in this manner. Despite being considered the ‘antibiotic drug of last resort’, significant bacterial resistance to vancomycin now manifests itself worldwide. In this paper we review recent progress made in understanding the lipid II-associated antibacterial characteristics of various naturally occurring compounds, with particular focus on the lantibiotic peptides.