In patients with cystic fibrosis (CF) lung damage secondary to chronic infection is the main cause of death. Treatment of lung disease to reduce the impact of infection, inflammation and subsequent lung injury is therefore of major importance. As Pseudomonas aeruginosa is the dominant pathogen in CF patients it has been the major target of all treatment strategies, possible antibiotic regimens and recommendations for years. More sophisticated antibiotic therapies introduced over the last decades have helped to improve the prognosis in cystic fibrosis, but then new multidrug-resistant pathogens emerged. We present a case of cystic fibrosis in a 16-year-old boy with pulmonary exacerbation due to colistin-resistant Stenotrophomonas maltophilia. This case raises some interesting questions regarding the antibiotic policy and treatment options in our country for patients with CF and multidrug-resistant strains. Colistin is used at present in Bulgaria as a strategic last option for the CF patients but with the advent of new more drug-resistant strains therapeutic approach should change - for instance, there should be restrictions imposed on the use of levofloxacin and trimethoprim/sulfamethoxazole which are regarded as "cheap and not so potent" antibiotics suitable for any infection and use them only in strict dependence on the respective culture results.