Individuals with the genetic disease cystic fibrosis (CF) accumulate mucus or sputum in their lungs. This sputum is a potent growth substrate for a range of potential pathogens, and the opportunistic bacterium Pseudomonas aeruginosa is generally most difficult of these to eradicate. As a result, P. aeruginosa infections are frequently maintained in the CF lung throughout life, and are the leading cause of death for these individuals. While great effort has been expended to better understand and treat these devastating infections, only recently have researchers begun to rigorously examine the roles played by specific nutrients in CF sputum to cue P. aeruginosa pathogenicity. This chapter summarizes the current state of knowledge regarding how P. aeruginosa metabolism in CF sputum affects initiation and maintenance of these infections. It contains an overview of CF lung disease and the mechanisms of P. aeruginosa pathogenicity. Several model systems used to study these infections are described with emphasis on the challenge of replicating the chronic infections observed in humans with CF. Nutrients present in CF sputum are surveyed, and the impacts of these nutrients on the infection are discussed. The chapter concludes by addressing the future of this line of research including the use of next-generation technologies and the potential for metabolism-based therapeutics.