Broad spectrum antitumor alkylating agents possess remarkably high Swain-Scott s constants, indicative of high discrimination for selectivity of reaction with strongly nucleophilic sites such as the N7 position of guanine. This review discusses relationships between s constants and intracellular product spreads, including the mutagenic products of O-alkylation; and structure-selectivity factors that determine s constants, such as reactivity, polarizability and softness of the alkyl substrate. We have achieved exaltation of s constants with selenone leaving groups, without the expected increased susceptibility to thiol-mediated cellular resistance, that contribute to the exciting promise of this new class of alkylating agents.