Looking at the prognosis of Cystic Fibrosis (CF) from the clinician's point of view is very relevant. Median predicted survival age of CF increased from 6 months when the disease was first described (1938) to 12 years in 1970 and over 35 years in 2010 in the United States of America (Davis, 2006). Three types of factors weigh on this prognosis, which is conditioned by lung disease: factors linked to the quality of care management, to genetics and to the environment. It has been estimated from studies in twins and siblings that the relative influence of the latter two is roughly equivalent. Though pollution may have increased in certain areas, and lighter forms of CF are now being detected by neonatal screening and in clinics where nasal potential measurements are widely available, their impact is limited and can not account for the spectacular changes in life expectancy. Thus, this improvement is due essentially to a better care management. Quality of care is the main determinant of CF prognosis. The question of prognosis is almost invariably the very first that parents of a newly diagnosed CF infant will ask their physician, whose task to answer in a sensitive and sensible fashion is by no means easy. This question is also at the heart of daily concerns of the clinician, who has to take its determinants into consideration not so much in view of their fascinating underlying mechanisms (e.g. modifier genes) but rather to the extent they can give grip to improved care.