The first highly selective C-H chlorination, bromination. and iodination of cubane (1) utilizing polyhalomethanes as halogen sources under phase-transfer (PT) conditions is described, Isomeric dihalocubanes with all possible combinations of chlorine, bromine, and iodine in ortho, meta, and para positions were also prepared by this method; m-dihalo products form preferentially. Ab initio and density functional theory (DFT) computations were used to rationalize the pronounced differences in the reactions of 1 with halogen (Hal(.)) vs carbon-centered trihalomethyl (Hal(3)C(.)) radicals (Hal = Cl, Br). For Hal(3)C radicals the C-H abstraction pathway is less unfavorable (DeltaG(298)(++) = 21.6 kcal/mol for Cl3C. and 19.4 kcal/mol for Br3C. at B3LYP/6-311+G**// B3LYP/6-31G**) than the fragmentation of the cubane skeleton via S(H)2-attack on one of the carbon atoms of 1 (DeltaG(298)(++) = 33.8 and 35.1 kcal/mol, respectively). In stark contrast, the reaction of 1 with halogen atoms preferentially follows the fragmentation pathway (DeltaG(298)(++) = 2.1 and 7.5 kcal/mol) and C-H abstraction is more unfavorable (DeltaG(298)(++) = 4.6 and 12.0 kcal/mol). Our computational results nicely agree with the behavior of 1 under PT halogenation conditions (where Hal(3)C(.) is involved in the activation step) and under free-radical photohalogenation with Hair (Della, E. W., et al. J.Am. Chern. Sec. 1992, 114, 10730). The incorporation of a second halogen atom preferentially in the meta position of halocubanes demonstrates the control of the regioselectivity by molecular orbital symmetry.