When liposomes are exposed to biological fluids, a dynamic coating of proteins immediately covers them. Similarly to the aura of plasma surrounding the Sun, plasma proteins are thought of as establishing an aura that surrounds each liposome, hence the phenomenon was dubbed ‘protein corona’. This natural functionalization includes proteins engaged from the blood that can interact with receptors (over)expressed on the plasma membrane of target cells, thus targeting the liposomes to their final destination. Exploiting the liposome–protein corona for targeting has the potential to revolutionize the treatment of many disorders and requires a deep understanding of the factors shaping the corona. Following incubation with human plasma (HP), here we manipulated this corona by using six liposomal formulations with systematic changes in lipid composition. The lipids we employed are among the most frequently used lipid species for drug and gene delivery applications in vitro and in vivo. The six liposome–protein coronas were thoroughly characterized by synchrotron small angle X-ray scattering, dynamic light scattering, zeta-potential and nanoliquid-chromatography tandem mass spectrometry experiments. We identified general principles shaping the liposome–protein corona and established clear-cut relationships between lipid species and classes of plasma proteins. This knowledge sets the basis for a rational manipulation of the protein corona for targeted drug delivery by liposome design.