Covering: 1975 up to the end of 2016The decline in the discovery and development of novel antibiotics has resulted in the emergence of bacteria that are resistant to almost all available antibiotics. Currently, polymyxin B and E (colistin) are being used as the last-line therapy against life-threatening infections, unfortunately resistance to polymyxins in both the community and hospital setting is becoming more common. Octapeptins are structurally related non-ribosomal lipopeptide antibiotics that do not exhibit cross-resistance with polymyxins and have a broader spectrum of activity that includes Gram-positive bacteria. This makes them a precious and finite resource for the development of new antibiotics against these problematic polymyxin-resistant Gram-negative pathogens, in particular Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. This review surveys the progress in understanding octapeptin chemistry, mechanisms of antibacterial activity and biosynthesis. With the lack of cross-resistance and their broad antibacterial activity, the octapeptins represent ideal candidates for the development of a new generation of polymyxin-like lipopeptide antibiotics targeting polymyxin-resistant 'superbugs'.