Multiple drug resistance (MDR) in Gram-negative bacteria represents one of the most intractable problems facing modern medicine. Colistin and polymyxin are cationic antimicrobial peptide antibiotics which permeabilise the bacterial outer membrane and have been used to treat infections. Resistance to these antibiotics is conferred by the modification of the lipid A headgroups with phosphoethanolamine (PEA) moieties resulting in a reduced negative charge of the bacterial surface and exclusion of the drug. This modification is carried out by the enzyme, lipid A PEA transferase (EptA). Recently a mobile colistin resistance determinant, mcr-1, encoding an EptA homologue was identified in MDR Escherichia coli. The crystal structure of EptA suggested the protein must undergo conformational changes to enable it to bind to different sized and shaped substrates. Crystallographic studies of the enzyme substrate complex as well as solution scattering and intrinsic fluorescence quenching studies undertaken have provided a deeper understanding of the conformational flexibility of the enzyme and the atomic details of substrate binding and endotoxin modification. Additionally, progress will be presented on the design and development of enzyme inhibitors.