Two enantiomers of the same chiral active pharmaceutical ingredients (APIs) often have different pharmacological properties. If one enantiomer can treat a disease, its counter enantiomer might be inactive or even toxic. For economic reasons, synthetic routes towards racemic mixtures are often preferred over direct asymmetric synthesis of the APIs but require resolution of the enantiomers. In this context, separation of enantiomers by means of crystallization has been used for decades and an increasing number of methods is nowadays available. Among them, Preferential Crystallization (PC) consists in the out-of-equilibrium stereoselective crystallization of an enantiomer from its racemic supersaturated solution. This is permitted by seeding the solution with the desired enantiomer which then crystallizes by secondary nucleation whereas the counter enantiomer remains in solution. However, PC requires that the mixture of enantiomers should crystallize as a physical mixture of enantiopure particles (i.e., a conglomerate) rather than as a racemic compound (i.e., a 1:1 stoichiometric compound). Yet, occurrences of conglomerates are much rarer than racemic compounds which drastically reduce the scope of PC. Chemical derivation or salt formation are commonly applied to “force” a mixture of enantiomer to crystallize as a conglomerate by changing the interactions at the solid state. It is also envisageable to use co-crystallization, i.e. to associate the chiral API with one or several achiral co-formers. “Preferential Co-crystallization” would indeed combine the benefit of co-crystallization with the advantage of PC. However, this strategy had not been applied until very recently. In this presentation, Preferential Co-crystallization will be applied to a family of chiral co-crystals based on chiral methyl xanthine derivatives, hydroxybenzoic acids and water. The drawbacks and benefits of using PC in co-crystal systems will be discussed using phase diagrams between enantiomers, crystal structures and process efficacy comparisons.