Thoracoscopic and open lung biopsies are being performed with increasing frequency in neonates and infants and are an important component of the diagnostic evaluation of respiratory compromise in these very young children. Diffuse lung disease in infancy includes a wide spectrum of developmental, genetic, inflammatory, infectious, and reactive disorders. The majority of the entities diagnosed in infancy (68%) in this retrospective lung biopsy series are seen almost exclusively in this age group and not in older children and adults. These include primary disorders of pulmonary and pulmonary vascular development, secondary disorders affecting prenatal and/or postnatal lung growth, genetic disorders of surfactant function, pulmonary interstitial glycogenosis, and neuroendocrine cell hyperplasia of infancy. Although the diagnostic approach to infant lung biopsies is guided primarily by the clinical history and imaging findings, all cases require careful assessment of alveolar growth, vascular architecture, interstitial cellularity, and histologic patterns associated with genetic abnormalities of surfactant metabolism. Recognition of one or more of these processes assists not only in treatment planning but also in further diagnostic evaluation and prognostication and may have implications for subsequent siblings and other family members. In this study, we have applied a classification system developed by a North American multicenter multidisciplinary group to lung biopsies seen at our institution and have used this material to describe and illustrate the spectrum of diffuse lung disease in infancy.