Chiral ligand-exchange chromatography (CLEC) first described in the late 1960s to early 1970s by Davankov and Rogozhin can be still considered as an elective choice for the direct enantioseparation of compounds endowed with chelating moieties. Among the numerous chelating species that have been evaluated as chiral selectors in ligand-exchange (LE) chromatography, a special role is played by a group of amino acids including proline, hydroxyproline, cysteine, phenylalanine, and penicillamine. More to the point, relevant chromatographic performances are also provided by amino alcohol-based chiral selectors, among which, those carrying a leucinol residue as the basic scaffold are worth to be mentioned. Among the various enantiomer chromatographic separation techniques, CLEC has been exploited in all the main techniques including a chiral mobile phase (CMP), a covalently bound chiral stationary phase (B-CSP), and a coated chiral stationary phase (C-CSP). It is the objective of this chapter to describe selected CLEC applications dealing with the above three distinct approaches.