Sequential cross-coupling on multihalogenated heterocycles is a particularly attractive strategy for the divergent synthesis of polysubstituted heterocycles, but the factors that govern the regioselectivity are not well understood. The present study shows that the selectivity in palladium-catalyzed cross-coupling reactions of heterocycles bearing multiple identical halogens is determined by both the energy to distort the carbon halogen bond to the transition-state geometry (related to BDE) and the interaction of the heterocycle pi* (LUMO) and PdL2 HOMO.