Mephedrone (4-methylmethcathinone), a constituent of the recreational substances known as “bath salts”, is a synthetic cathinone that can produce auditory and visual hallucinations, as well as problematic cardiovascular effects. This study compared the discriminative stimulus effects of mephedrone (0.32–10 mg/kg) with other prototypical drugs of abuse: cocaine (0.56–32 mg/kg), d-amphetamine (0.18–3.2 mg/kg), ketamine (1.8–18 mg/kg), phencyclidine (PCP, 1–5.6 mg/kg), heroin (1–10 mg/kg), 2,5-dimethoxy-4-iodoamphetamine (R-DOI, 0.1–1 mg/kg), Δ9-tetrahydrocannabinol (Δ9−THC 0.56–5.6 mg/kg), 3,4-methylenedioxyamphetamine (MDA, 0.32–5.6 mg/kg), methylphenidate (1–10 mg/kg), and 3,4-methylenedioxypyrovalerone (MDPV, 0.56–5.6 mg/kg). The discriminative stimulus effects of mephedrone were also assessed after administration of the sigma receptor antagonist rimcazole (0.32–10 mg/kg), the relatively selective norepinephrine transporter (NET) inhibitor desipramine (1.8–18 mg/kg), and the selective serotonin transporter (SERT) inhibitor fluoxetine (1–18 mg/kg). Initially, rats were trained to discriminate an intraperitoneal injection of mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 schedule of food presentation. Following training, cumulative doses of mephedrone and the other drugs were administered to test for substitution (80% drug-lever responding). Of the drugs tested, including those that were tested in combination with mephedrone (i.e., rimcazole, desipramine, and fluoxetine), only cocaine fully substituted for mephedrone without substantially decreasing response rate. In addition, the three drugs administered in combination with mephedrone shifted the cumulative dose-effect curves leftward (percent drug-lever responding) and down (response rate), although fluoxetine did so in a dose-dependent manner ranging from antagonism to potentiation. In summary, the discriminative stimulus effects of mephedrone were most similar to those for the central nervous system (CNS) stimulant, cocaine, and SERT and DAT activity were necessary for these effects.