Genetic and phenotypic complexity has been described for diseases of varied etiology. Groups of patients with varied phenotype can be used in association studies as an initial approach to identify contributing loci. Although association studies have limitations, their value is enhanced by using candidate genes with functions related to disease. Surfactant proteins have been studied in the etiopathogenesis of neonatal pulmonary diseases. SP-A and SP-B polymorphisms are found at a higher frequency in certain groups of patients with respiratory distress syndrome (RDS), and SP-B mutations are linked to the pathogenesis of congenital alveolar proteinosis (CAP). Phenotypic heterogeneity is observed for both CAP and RDS. The available data suggest that a number of factors contribute to the etiology of CAP and RDS and, therefore, a multidisciplinary approach of clinical, genetic, epidemiologic, and statistical considerations is necessary for an in-depth understanding of the pathophysiology of these and other pulmonary diseases.