Abstract The importance of the overlapping between the highest occupied (HO) molecular orbital (MO) of an electron donor and the lowest unoccupied (LU) MO of an electron acceptor in determining the favorable position and spatial direction of a chemical reaction is emphasized by setting up the following auxiliary principles: the principle of a positional parallelism between the chargetransfer and the bond-interchange, the principle of a narrowing of the inter-frontier energy-level separation, and the principle of a growing frontier density along the reaction path. These subprinciples work in a cooperative manner to enable us to arrive at this general governing principle: most of the chemical interactions are liable to occur at the position and in the direction where the overlapping of the HO and the LU of the respective reactants is at its maximum; in an electron-donating reactant, HO predominates in the overlapping interaction with the MO’s of the other reactant, whereas LU does so in an electron-accepting reactant; in the reactants which possess singly-occupied (SO) MO’s, these play the part of HO or of LU, or of both. These particular MO’s, HO, LU, and SO are “generalized frontier orbitals” in chemical reactions. This principle is applied to uni-centric reactions to give the orientation rule; if it is applied to multi-centric reactions, the stereoselection rule is obtained.