A new approach to model and interpret the separation of amino acid enantiomers is described. The descriptive structure-separation relationship (DSSR) study of a set of amino acid enantiomer couples analyzed with two chiral selectors S-benzyl-(R)-cysteine ((R)-SBC) and S-trityl-(R)-cysteine ((R)-STC) has been performed with the aim to highlight the molecular properties of the analyte affecting the enantiodiscrimination process. Although with some exceptions, the classification models obtained with (R)-STC indicate that the partial positive surface area (PPSA-1) is the suitable descriptor to account for the separation of both (R)- and (S)-enantiomers. On the other hand, two different descriptors characterize the separation process with (R)-SBC. While fractional negatively charged partial surface area (FNSA-3) results the discriminating descriptor for (R)-enantiomers, the relative polar surface area (RPSA) is able to best discriminate among (S)-enantiomers.