Patients with cystic fibrosis (CF) exhibit significant variability in the course and severity of the disease, and this variability is best interpreted in the context of an interaction between genetic and nongenetic determinants. While a small number of patients with "mild" mutations in the CF transmembrane conductance regulator gene clearly have less severe disease, for the general population of patients with CF the strongest predictor of severity of clinical course appears to be socioeconomic status (SES). Low SES probably exerts an influence via the convergence of detrimental environmental influences on outcome such as environmental tobacco smoke, poor nutrition, and stress. Other important predictors that appear to be independent of SES include gender and acquisition of airway pathogens such as Pseudomonas aeruginosa and Burkholderia cepacia complex. Finally, effective provision of medical interventions is an important determinant of outcome, and this is affected primarily by patient adherence (which bears a poorly defined relationship to SES), and attendance at a CF care center that utilizes a system of care that allows optimal delivery of evidence-based interventions.