Antidepressant drugs have greatly improved the outcome of depression but approximately 50% of patients do not respond to these drugs. Serotonin (5-HT) is a key neurotransmitter in depression. A number of studies suggested an association between the response to selective 5-HT reuptake inhibitors (SSRIs), the mainstays in the treatment of depression, and variants in genes modulating central 5-HT neurotransmission such as the 5-HT transporter, 5-HT receptors, the recently discovered isoform of tryptophan hydroxylase (TPH-2), the enzyme responsible for the synthesis of 5-HT in the brain. The focus of the present paper is to summarize recent mouse studies that have boosted new interest in the role of 5-HT in the resistance to antidepressant drugs and the mechanisms involved. The results indicate that an impaired 5-HT transmission contribute to the lack of effect of SSRIs in the forced swimming test, a widely used procedure to assess the antidepressant potential of compounds and suggest that 5-HT precursor loading and prevention of the activation of negative feedback mechanisms controlling 5-HT neurons may be useful to improve the response to SSRIs.