Stimulants are a highly efficacious and safe treatment for attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients responding well if two different stimulants (amphetamine and methylphenidate) are used. Nonetheless, a subset of ADHD patients will either fail to respond to stimulants or have side effects that preclude their use (tics, severe loss of appetite, marked insomnia). For such patients, there are a number of non-stimulant agents that serve as second-line treatments. Tricyclic antidepressants (TCAs) are the most studied of these drugs. They are superior to placebo in the treatment of ADHD and may reduce abnormal movements in patients with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth, and constipation. Bupropion is superior to placebo in the treatment of ADHD and has a more favorable side-effect profile than the TCAs. A new selective norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious in the treatment of ADHD and has recently received an approvable letter from the Food and Drug Administration. The a-agonists clonidine and guanfacine have also been used as alternative agents in ADHD, though the controlled data are more limited. A recent controlled clinical trial suggests a combination of methylphenidate and clonidine has advantages in the treatment of comorbid ADHD and tics over either medication alone. Clinical guidelines for each of these agents, as well as their use in combination with stimulants in comorbid conditions, will be discussed.