Pulmonary surfactant protein B (SP-B) is a 79 amino acid peptide that is intimately associated with surfactant phospholipids in the alveolar airspace. Mutations of the SP-B gene that result in complete absence of SP-B are invariably fatal in the neonatal period. The pathology associated with SP-B deficiency suggests that SP-B plays a critical role in integrating the synthesis, assembly and metabolism of the surfactant complex. A strategy is described to elucidate the role of SP-B in surfactant homeostasis by characterizing the pathophysiology associated with cell specific expression of SP-B constructs in vivo. Human SP-B constructs, under control of lung cell-specific promoters, were expressed in SP-B knockout mice in order to achieve expression of the human transgene in a null background. The effect of transgene expression on lung structure and function was assessed by biochemical, morphological and physiological analyses of the surfactant system in fetal and postnatal offspring.