Cystic fibrosis (CF) is a multisystem disease. Some of this is accounted for by CF transmembrane regulator (CFTR) dysfunction in individual organs but in some cases this is compounded by the effects of systemic inflammation. The inflammation is in response to the chronic infection in the airways and is particularly important as a contributor to CF-related bone disease, CF-related diabetes mellitus, CF-related arthropathy, and vasculitis. Preventing these multisystem complications is difficult. Aggressive specific therapies to treat complications is critically important to maintain nutrition, stop the damaging effects of diabetes, and improve bone mineral density. Aggressive treatment of lung disease to reduce systemic inflammation is likely to be of benefit in preventing the development of CF-related bone disease and may be beneficial in at least delaying the onset of CF-related diabetes. Aggressive treatment of pulmonary infection and inflammation in conjunction with holistic management plans to treat specific organ diseases is an important strategy in improving morbidity and reducing mortality in people with CF.