Cystic fibrosis (CF) is one of the most common genetic disorders among Caucasians. CF patients are susceptible to chronic lung infections caused by diverse microorganisms, therefore CF should be regarded as a polymicrobial disease. Iron availability in the host is very limited, an obstacle for successful infection by pathogens. Siderophores are iron-binding low-molecular-weight compounds enabling microorganisms that produce them to grow under iron-limiting conditions. The aim of this review is to highlight the role of siderophores as virulence factors in CF pathogenesis, the siderophore ecology in CF lungs, the protective host mechanisms leading to iron-limiting conditions, and finally how siderophore-mediated iron uptake could be exploited for potential therapeutic interventions in cystic fibrosis.