For large reactive systems, the calculation of energies can be simplified by treating the active part with a high-level quantum mechanical (QM) (ab initio or density functional) approach and the environment with a less sophisticated semiempirical (SE) approach, as an improvement over the widely used hybrid quantum mechanical/molecular mechanical (QM/MM) methods. An example is the interaction between an active region of an enzyme and its immediate environment. One such method is the original "Our-own-N-layer Integrated molecular Orbital+Molecular Mechanics (ONIOM)" approach. In this paper, the interaction between the QM and SE region is described explicitly by two different schemes. In the iterative QM/SE schemes (QM/SE-I), the electrostatic interaction and polarization effects are introduced explicitly for both the QM and SE atoms by a self-consistent procedure based on either polarizable point charges or the electron density. In the noniterative QM/SE scheme, based on the ONIOM model (QM/SE-O), the exchange (Pauli repulsion) and charge transfer effects are taken into account at the SE level, in addition to the explicit electrostatic interaction and polarization between the two regions. Test calculations are made on a number of model systems (including small polar or charged molecules interacting with water and proton transfer reactions in the presence of polar molecules or an extended hydrogen-bond network). The quantitative accuracy of the results depend on several parameters, such as the charge-scaling/normalization factors for the SE charge and the QM/SE van der Waals parameters, which can be chosen to optimize the result. For the QM/SE-O approach, the results are more sensitive to the quality of the SE level (e.g., self-consistent-charge density-functional-tight-binding vs AM1) than the explicit interaction between QM and SE atoms.