Systemic diseases affecting the lung are fortunately relatively rare in paediatric practice. A number of conditions do, however, cause significant respiratory complications, which can result in serious morbidity and mortality in this age group. These include connective tissue disorders such as systemic lupus erythematosus, dermatomyositis and scleroderma, inherited connective tissue disorders such as Ehlers–Danlos and Marfan’s syndrome, lysosomal storage disorders such as mucopolysaccharidoses, familial dysautonomia, Langerhans cell histocytosis, pulmonary lymphangiomatosis, sarcoidosis and sickle cell disease. The investigations of these conditions are often complex but form part of the overall multisystem review of each individual patient. Treatment is individualised but often requires the extended use of corticosteroids and other immunosuppressants. The outcome is variable and depends on the ability to control the underlying condition. Long-term chronic lung damage is not unusual and these diseases, when they affect the lung, carry a small but significant mortality.