Individuals affected by cystic fibrosis experience dysfunction of multiple organ systems. Most morbidity and mortality are associated with progressive obstructive lung disease that is accentuated by periodic pulmonary exacerbations—acute declines in pulmonary function. Treatment of a pulmonary exacerbation must address multiple factors that may contribute to the worsening lung function. Culture and sensitivity data from lower airway secretions should be used to guide antimicrobial therapy. An aggressive airway clearance regimen should be individualized to the needs of each patient Nutritional supplementation improves lung function by satisfying increased energy needs and enhancing immune function. Management of acute exacerbations can also be complicated by other medical conditions such as hypoxemia, right heart failure, pneumothorax, hemoptysis, allergic bronchopulmonary aspergillosis, and pregnancy. Therefore, treatment of infection alone may not be sufficient in this patient population. Unfortunately, even the multidisciplinary and multisystem approach to the treatment of pulmonary exacerbations may not restore lung function to a preexacerbation baseline or prevent the overall relentless loss of lung function seen in patients with cystic fibrosis.