Background: Small air filled peripheral subpleural cysts are a well described feature of pulmonary anatomy at computerised tomographic (CAT) scan in children with Trisomy 21, yet only anecdotally described in association with other pathologies. The significance of these cysts is unknown. Objective: To investigate and explore the pathogenesis of these subpleural cysts in children. Materials and Methods: A retrospective review of 16 cases with subpleural cysts diagnosed on CT chest was performed. The distribution, location and ancillary CT findings were recorded. Hospital charts were reviewed for clinical details, especially cardiac abnormalities, pulmonary artery hypertension (PAH) and genetic associations. Histopathological and clinical correlative data were recorded. Results: 11/16 children (69%) were found to have an underlying chromosomal or genetic abnormality, six of whom had Trisomy 21. The remaining 5/16 cases (21%) had miscellaneous disorders without an identifiable genetic basis. The most common co-morbidities were cardiac abnormalities (81%) and PAH (62.5%). Regardless of their underlying etiologies, the cysts were present bilaterally in most cases (14/16, 88%). We observed both the postnatal development and the progression of cysts in our cohort . On long term follow-up, there were five deaths (31%) and six cases (38%) requiring maintenance oxygen therapy due to chronic hypoxia. Two cases (12.5%) became completely asymptomatic after correction of their underlying abnormalities. Conclusion: Subpleural cysts are not exclusive to Trisomy 21 and may be seen in other inherited or acquired causes, likely due to altered alveolar growth. We suspect these cysts are a sign of an underlying developmental disorder with variable clinical effect, especially in children with congenital cardiac disease.