Antibiotic resistance has reached crisis point in many hospitals around the world. The majority are swamped with meticillin-resistant Staphylococcus aureus (MRSA), and many with multidrug-resistant (MDR) Gram-negatives. Whilst there are good treatment alternatives available for serious infections due to MRSA, mortality rates remain high. For MDR Gram-negatives the situation is more complex and worrying. There are few, if any, new agents in development that can be expected to benefit the situation in the next decade. Moreover, extreme (or extensive) drug-resistant and even pandrug-resistant Gram-negative infections are increasingly being described. Although definitions are confused in this area, reports suggest that patients in some intensive care units are dying from lack of availability of any antibiotic active against certain strains of Pseudomonas aeruginosa and Acinetobacter baumannii. A better understanding of the molecular basis of resistance is urgently needed if it is to be successfully overcome. Moreover, we urgently need better global early warning systems to detect new resistances and put mechanisms in place for their control.