Numerous authors have demonstrated uptake of micro- and nanospheres, consisting of natural or synthetic polymeric materials from the gastrointestinal tract over the past two decades. The exploitation of particulate carrier systems for the delivery of peptides and other hydrophilic macromolecules via the oral route remains a challenging task due to morphological and physiological absorption barriers in the gastrointestinal tract. This review examines recent progress in the field of nanoparticle uptake from this site of administration. Since most studies have been performed with poly(styrene) particles of different sizes relatively little is known about both the effect of physicochemical particle properties critical for absorption after peroral application, and the mechanisms of gastrointestinal particle uptake. Apart from particle size, type and composition of the polymers used for micro- or nanoencapsulation are crucial for an uptake and transport across mucosal barriers. Factors such as particle surface charge and hydrophilic/hydrophobic balance of these polymeric materials have not been investigated systematically since adjustment of these particle properties is almost impossible without synthetic modification of the polymers. The current findings will be reviewed and compared to those obtained with nanoparticles consisting of a novel class of charged comb polyesters, poly(2-sulfobutyl-vinyl alcohol)-graft-poly(D,L-lactic-co-glycolic acid), SB-PVAL-g-PLGA, allowing adjustment of physicochemical nanoparticle properties with a single class of polymers.