The majority of cystic fibrosis (CF)-related morbidity and mortality is caused by pulmonary damage due to recurrent and chronic infections. Considerable improvements in the survival of individuals with CF have been achieved in recent decades, some of which may be due to better management of common pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. While the search continues for the optimal approach for prophylaxis, eradication and maintenance treatment of infections, there are several unanswered questions, posing dilemmas related to various therapeutic choices. Microbes pose additional challenges by adapting to CF lungs and developing treatment resistance. Several new, highly antimicrobial-resistant pathogens have emerged. Their pathogenic role in the progression of CF lung disease is not yet clear and effective treatment approaches have not been defined. There is an urgent need for well-designed comparative clinical trials of new antibiotic strategies.