Pseudomonas aeruginosa is one of the most dreaded Gram-negative bacterial pathogens in hospitals. Not only it is among the most frequently isolated Gram-negative organisms in bloodstream and wound infections, pneumonia, intra-abdominal-sepsis and urogenital-sepsis, but also it is frequently found in patients with comorbid illnesses and compromised by in-dwelling catheters, tubes and surgery where mortality rates of more than 60% have been reported. Besides its intrinsic resistance to a number of widely used antibiotics, Pseudomonas also managed to acquire resistance via additional mechanisms, including target mutations, increased expression of efflux pumps and of antibiotic-degrading enzymes. Taken together, the increased incidence in certain types of infections, the increased use of invasive devices in the hospital as well as the increased frequency of multi-resistant Pseudomonas strains, have clearly led to a shortage of treatment options for nosocomial Pseudomonas infections. Even the recommended combination therapy of an antibiotic of the beta-lactam class together with an aminoglycoside or a fluoroquinolone, is no longer always successful and sometimes a polymyxin has to be given as last resort. Despite growing concerns of clinicians and medical societies about the very limited number of novel drugs in the pipeline to fight multi-resistant Pseudomonas strains, only a very small number of novel anti-Pseudomonas drugs are currently in late stage of pre-clinical or clinical development. However, and possibly as a reflection of the magnitude of the problem, quite a variety of approaches are being pursued. Among these are next-generation analogues of successful antibiotic classes (e.g. novel beta-lactams and combinations of novel beta-lactamase inhibitors with known penicillins or cephalosporins), antibodies, phages and selective peptides. It is to be hoped that a number of these novel drugs will show clinical utility and reach the market over the next 6-10 years.