A DFT study by using B3LYP/6-311G+(dp) level on molecular orbital of some aromatic and heteroaromatic compounds shows that ERE and Bird indexes fit with (π₁-π₂) + (π₁-π₃). On the contrary molecular susceptibility does not fit. χм and ERE fit with the quantity π₁ + (π₂-π₃). The ISE of some pentaatomic aromatic heterocyclic compounds showed some overestimation in the case of furan and oxazole and some different underestimation in the case of thiophene and thiazole ring. The low reactivity of pyridine, pyridazine, pyrazine, pyrimidine, and purine towards electrophilic substitution reactions can be explained assuming a frontier orbitals control of the reaction. DFT study of the molecular orbitals of these molecules shows that the HOMOs of these substrates are not π orbitals. Furthermore, the change in the reactivity observed in pyridine-N-oxide, in activated pyrimidines, and in activated purines can be explained considering that, in this case, the HOMOs are π orbitals. DFT calculations of the frontier orbitals of aromatic and heteroaromatic compounds allows to explain the observed reactivity. The LUMO of bromobenzene does not allow aromatic substitution because the atomic coefficient on the carbon atom bearing the substituent is zero. The low observed reactivity can be due to the role of NLUMO. The LUMOs of 2,4-dinitrofluorobenzene, 4-chloropyridine, 4-chloropyrimidine, 4-chloropyri-dazine, and 2-chloropyrazine allow the nucleophilic substitution reactions. The LUMO of 2-bromofuran is not a π* orbital, and the low observed reactivity is due to the participation of the NLUMO. The LUMOs of 2-chlorothiophene, 2-chlorooxazole, and 2-chlorothiazole allow aromatic substitutions. Both the LUMO and NLUMO of 2-chloro-N-methylpyrrole are not π* orbitals. The low reactivity of 2-chloro-N-methylimidazole is due to the participation of the NLUMO.