Bacterial respiratory infections are the main reason of morbidity and mortality among cystic fibrosis (CF) patients. In early childhood, the respiratory infections are due to Staphylococcus aureus and Haemophilus influenzae. In older CF patients, pathogenic Gram-negative bacteria like Achromobacter xylosoxidans, Burkholderia cepacia complex and especially Pseudomonas aeruginosa are more frequently seen. P. aeruginosa is a turning point in the respiratory disease in CF and its predominance increases with age. Bacteria use a variety of two-component systems (TCS) to differentially express virulence factors involved in both acute and chronic infections. Here, we review bacterial TCS as targets for antibacterial treatment for CF patients.