The use of exogenous surfactant (ES) is an essential component for prevention and treatment of hyaline membrane disease (HMD). The ES available for clinical use are of two therapeutic classes: natural surfactants prepared from mammalian lung and artificial surfactants. The choice between these two classes of ES is controversial. In this overview, we present the arguments in favour of the preferential use of natural ES. The presence of hydrophobic specific proteins (SP-B and SP-C) provides to natural ES better surface tension properties than artificial ES. The in vitro greater efficacy of natural ES has been confirmed in vivo in experimental models of surfactant deficiency, human pharmacodynamic studies, and comparative clinical trials. Furthermore, the excellent clinical tolerance and harmlessness of natural ES has been firmly established. A meta-analysis of the comparative clinical trials between natural ES and one artificial ES (enrolling as many as 4400 babies treated for HMD) suggests that the use of natural ES compared to this artificial ES significantly reduces the neonatal mortality by 20%. In conclusion, all these arguments are in favor of the preferential use of natural ES for prevention and treatment of HMD.