This chapter discusses preclinical and clinical evidence for agonist-like pharmacotherapy for stimulant dependence. Four converging lines of evidence, one preclinical and three clinical, support an agonist approach to pharmacotherapy of stimulant dependence as one component of the armamentarium. Three distinctive lines of clinical activity provide evidence that stimulant dependence can be ameliorated with stimulant administration. A novel pharmacologic strategy being examined for cocaine dependence utilizes disulfiram, an agent long used for alcohol dependence treatment. Disulfiram (DA) decreases alcohol consumption through the inhibition of the enzyme aldehyde dehydrogenase, resulting in accumulation of acetaldehyde and aversive consequences. It is found that data strongly indicate a role for enhanced DA transmission in the appetitive effects of psychostimulants and suggest targeting of the DA system in agonist substitution therapy. It is suggested that the ideal agonist substitution therapy, particularly to attenuate active drug use, should target the DA, 5-HT, and NE systems, as this broad-based strategy has several advantages. It is found that use of an oral cocaine preparation as an agonist substitution therapy is limited by many theoretical and practical difficulties.