Trazodone is an atypical antidepressant drug that is commonly referred to as a serotonin (5-hydroxytryptamine; 5-HT) uptake inhibitor. However, the most potent pharmacological effect of trazodone appears to be antagonist action at 5-HT2/1C receptors. This is in contrast to fluoxetine, for which inhibition of 5-HT uptake is the most potent pharmacological action. The effects of trazodone and fluoxetine on several antidepressant drug screens are mediated by antagonist action at 5-HT2 receptors and inhibition of 5-HT uptake, respectively. While fluoxetine is an effective agent for the treatment of major depression, obsessive-compulsive disorder (OCD) and panic disorder, trazodone does not appear to be effective in the treatment of OCD and panic disorder. In addition, trazodone and fluoxetine differ in humans with respect to their effects on sleep and weight. Taken together, the preclinical and clinical data suggest that trazodone acts as an antidepressant via antagonist action at 5-HT2/1C receptors, while fluoxetine likely acts as an antidepressant via inhibition of 5-HT uptake.