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Despite dramatic improvements over the last several decades, tremendous variation exists in cystic fibrosis (CF) health outcomes. Genetic explanations for variations in disease progression are a promising source of information regarding disease biology and pathophysiology, but an understanding of nongenetic factors provides more immediate tools for improving disease outcomes.The clinical course of CF for any individual with CF is determined by the interaction of genetic endowment (including CFTR and modifier genes), the physical environment (including environmental tobacco smoke, outdoor pollution, and pathogenic microorganisms), the sociodemographic, cultural, and family context (which mediates stress, social support, and disease self-management skills), and variations in delivery and acceptance of healthcare treatments. The evidence linking socioeconomic status (SES) with CF outcomes continues to be strong, and appears to be primarily due to associations with environmental and sociocultural stressors and disease-management behaviors rather than barriers in access to healthcare.Attempts to eliminate detrimental environmental exposures, improve disease self-management skills, and ensure consistently optimal healthcare practices will likely decrease variations in outcomes including SES-related disparities. Low SES is an important marker of adverse exposures and outcomes which are present throughout the CF population.