Several studies have suggested that antidepressants might be beneficial in the treatment of patients with functional gastrointestinal disorders. This commentary discusses the results of a high-quality, multicenter, randomized, double-blind, placebo-controlled trial that showed no benefit of the antidepressant venlafaxine over placebo in the treatment of a large group of patients with functional dyspepsia. Moreover, venlafaxine was poorly tolerated by a considerable number of patients. The routine use of venlafaxine and other serotonin and norepinephrine reuptake-inhibitor antidepressants to treat patients with functional dyspepsia is, therefore, not recommended. Whether certain subgroups of patients, particularly those with anxious or depressive psychiatric comorbidities, might benefit from treatment with this class of antidepressants, however, remains to be elucidated. Antidepressants with different mechanisms of actions, for example mirtazapine, might still prove beneficial for the treatment of functional dyspepsia, but no clinical studies have yet investigated the efficacy of these drugs in this setting.