We report the case of a 22-year-old male who exhibited severe manic behavior shortly after beginning treatment with modafinil and venlafaxine for narcolepsy with cataplexy. The manic episode persisted several weeks after medication cessation and required management with a mood stabilizer. Reinstitution of modafinil and an alternate antidepressant for recurrent sleepiness and cataplexy was well tolerated and very effective. Sleep physicians should be aware that psychostimulants, including modafinil, and antidepressant medications commonly prescribed for treatment of narcolepsy may precipitate mania in patients with underlying bipolar disorder.