The adsorption of serum proteins at phospholipid surfaces was investigated in relation to uptake of intravenously administered colloidal drug carriers. In particular, an approach based on the use of surface-modified flat substrates for investigations of the adsorption pattern by in situ ellipsometry and surface plasmon resonance is discussed. Similar results regarding protein adsorption were obtained for phosphiolipid layers prepared through spin-coating, Langmuir-Blodgett deposition, and liposome adsorption. Furthermore, a good agreement was found between the adsorption at the model surfaces, on one hand, and at oil-in-water emulsion droplets, on the other, suggesting that curvature effects on the adsorption are minor. By the use of this approach, the adsorption of a number of proteins at a range of surfaces was investigated. Also mixed (phospho)lipid layers were studied, as was the adsorption from diluted serum and plasma. The results obtained are discussed in relation to the effects of the surface properties on the performance of colloidal drug carriers.