Nano-sized particles (NSPs) have a diameter of less than 100 nm. When inhaled, they preferentially deposit in the deeper lung, where pulmonary surfactant covers the thin aqueous lining layer. Thus, pulmonary surfactant is the initial contact where NSPs impinge. This can lead to various consequences. For example, binding of NSPs to single surfactant components like phospholipids or surfactant proteins can occur, which might modulate toxic particle effects. Moreover, particle clearance can be modulated. Furthermore, the biophysical surfactant function itself can be disturbed by interaction with NSPs. In addition, surfactant displaces particles into the aqueous hypophase of the lining layer, where they can come into contact with type II pneumocytes. This interaction has been suggested to affect pulmonary surfactant metabolism. The potential interactions of nano-sized particles with the pulmonary surfactant system and the effects on biophysical surfactant function, surfactant metabolism, particle clearance, and on particle-induced toxicity are reviewed.