Tri‐o‐thymotide (TOT) clathrates are enantiomorphous and enantioselective (chiral cages). It was shown that an external molecular reactant can diffuse into the TOT host crystal lattice and reacts with the included molecule (guest) in characteristic ways, differing from those occurring in liquid solutions. Several aspects of the action of hydrogen halides (HCl, HBr) on the chemical behavior of included oxiranes were investigated for solid‐gas and solid‐liquid (aqueous) systems. Under well established experimental conditions, these reactions gave regiospecifically one target product and were asymmetric. The included substrate underwent first an acid‐catalyzed allylic isomerization that is cage‐specific and mostly quantitative. In sheer contrast, strong basic conditions were required to promote, in reduced yield, the analogous transformation in solution. The regiospecificity and enantioselectivity of several intra‐crystalline conversions allowed the accurate determination of the absolute configuration of several guest molecules. Kinetic measurements were achieved that disclosed some striking features of this new type of heterogeneous reactions. Tentative models for the cage stereoselective mechanisms are briefly discussed.