Major depression and related depressive disorders are highly prevalent in the general population and even more so in patients with epilepsy. Yet depression in these patients remains underdiagnosed and undertreated. This is particularly worrisome as depression has greater negative impact on quality of life than seizure frequency. Additionally, depression is associated with poorer seizure control, and the risk of suicide in patients with epilepsy is greatly increased. Reluctance to treat depression results from the traditional belief that antidepressants should be restricted in epilepsy because of a supposed decrease in seizure threshold. However, there is growing evidence that many antidepressants rather have anticonvulsant effects. Experimental studies show that in critical brain regions such as the frontal lobes and the limbic system enforced serotonergic circuits increase seizure threshold. Clinical data suggest that modern antidepressants may reduce seizure frequency in patients with pharmacoresistant epilepsy. Here we review the concept that selective reuptake inhibitors of serotonin (SSRIs) have a positive effect on the mood disorder as well as on epilepsy. When adhering to the usual precautions, treatment with SSRIs in patients with epilepsy and depression is safe and should not be withheld.