A nonlocal (pair site) reactivity scheme is developed and tested. The theory is cast in terms of the first-order Fukui response function f(r,r＇), previously proposed by Fuentealba and Pan: [J. Chem. Phys. 1991, 94, 5559]. A change of variables is introduced by using the softness s(r) and t(r) = [partial derivative s(r)/partial derivative N](v(r)) (the variation of softness with respect to the changes in the total number of electrons N at constant external potential v(r)) that leads to a simple expression for the variation of the Fukui function at site k, namely Delta f(k)(-) = A(k)(-) = A(k)(-)delta v(k) -t(k)(-)Delta mu for an electrophilic attack. The first term describes a local contribution, proportional to the variation of the electrostatic potential that can be induced, for example, by the approach of an electrophilic agent, with a variable global softness coefficient thereby incorporating higher (third) order derivatives of the electronic energy. The second term contains nonlocal information implicitly involving a second reactive site that is expressed in terms of the variations to the electronic chemical potential Delta mu, accounting for the charge transfer related to the electrophile/nucleophile interaction. New reactivity indexes t(k)(+), t(k)(-), t(k)* are derived. They are associated with nucleophile, electrophile, and radical attacks. The theory applies to gas-phase reactivity. Solvent effects are introduced in the continuum approach to the surrounding medium. The resulting model is applied to study the chemistry of the enolate ion in the gas and solution phases. In the gas phase, an inversion of f(r) in the vicinity of the transition structure is observed that leads to alkylation at the oxygen atom. Incorporation of two water molecules to mimic solvent effects changes the gas-phase pattern of reactivity, and alkylation at the alpha-carbon is predicted in solution, in agreement with the experiments.