The chapter discusses the role of *Pseudomonas aeruginosa* and *Burkholderia cepacia* in cystic fibrosis (CF) lung disease. It begins with an introduction to CF, highlighting the importance of understanding both the genetic defect underlying CF and the specific bacteria that infect CF patients. The chapter then delves into the microbiology of CF, explaining how the CF lung environment is unique and how it predisposes patients to chronic microbial colonization, particularly by *P. aeruginosa*. The focus shifts to *P. aeruginosa*, the most common pathogen in CF patients. The chapter details the historical association between *P. aeruginosa* and CF lungs, noting that mucoid strains of *P. aeruginosa* are almost diagnostic of CF. It explores the transition from nonmucoid to mucoid strains, which is believed to be a critical step in the progression of chronic infection. The mechanisms underlying this transition, including the role of alginate production, are discussed in detail. Alginate is described as a major virulence determinant, contributing to biofilm formation, immune evasion, and antibiotic resistance. The chapter also examines the relationship between conversion to mucoidy and chronic colonization in the CF lung, suggesting that this transition is influenced by host factors such as CFTR mutations and bacterial factors like the ability to adhere to undersialylated receptors on epithelial cells. The implications of mucoidy for patient prognosis and the challenges of treatment are highlighted. Finally, the chapter touches on *B. cepacia*, another opportunistic pathogen that has emerged as a significant concern in CF patients. It discusses the transmission, identification, and pathogenesis of *B. cepacia*, emphasizing its potential to cause severe infections in CF patients. The conclusion emphasizes the complexity of CF lung disease and the need for continued research to improve understanding and treatment of these infections.The chapter discusses the role of *Pseudomonas aeruginosa* and *Burkholderia cepacia* in cystic fibrosis (CF) lung disease. It begins with an introduction to CF, highlighting the importance of understanding both the genetic defect underlying CF and the specific bacteria that infect CF patients. The chapter then delves into the microbiology of CF, explaining how the CF lung environment is unique and how it predisposes patients to chronic microbial colonization, particularly by *P. aeruginosa*. The focus shifts to *P. aeruginosa*, the most common pathogen in CF patients. The chapter details the historical association between *P. aeruginosa* and CF lungs, noting that mucoid strains of *P. aeruginosa* are almost diagnostic of CF. It explores the transition from nonmucoid to mucoid strains, which is believed to be a critical step in the progression of chronic infection. The mechanisms underlying this transition, including the role of alginate production, are discussed in detail. Alginate is described as a major virulence determinant, contributing to biofilm formation, immune evasion, and antibiotic resistance. The chapter also examines the relationship between conversion to mucoidy and chronic colonization in the CF lung, suggesting that this transition is influenced by host factors such as CFTR mutations and bacterial factors like the ability to adhere to undersialylated receptors on epithelial cells. The implications of mucoidy for patient prognosis and the challenges of treatment are highlighted. Finally, the chapter touches on *B. cepacia*, another opportunistic pathogen that has emerged as a significant concern in CF patients. It discusses the transmission, identification, and pathogenesis of *B. cepacia*, emphasizing its potential to cause severe infections in CF patients. The conclusion emphasizes the complexity of CF lung disease and the need for continued research to improve understanding and treatment of these infections.