Penicillin binding proteins (PBPs) have been a fantastic target for b-lactam drug discovery and development for decades. The development of resistance via b-lactamase enzymes that destroy the drug before reaching its target have directed research in the pharma industry into b-lactam, b-lactamase combinations which have attempted maintained the efficacy of these drugs but new approaches are desperately needed. Recently the field of bacterial cell biology has undergone renaissance of understanding and new approaches that shed new light onto the role of the various PBPs in bacterial cells. We now have a new understanding of which enzyme are most important for bacterial survival and what context they work in. I will present data and thoughts for discussion on new lines of research that may revitalise programmes of drug discovery against the lipid II polymerisation activity required for bacterial peptidoglycan biosynthesis in these key PBP partnerships.