Serotonin-norepinephrine-reuptake inhibitors (SNRIs) and selective serotonin-reuptake inhibitors (SSRIs) belong to a new generation of antidepressants used in the treatment of depression and other mood disorders. SSRIs act as reuptake inhibitors primarily via the inhibition of the neuronal reuptake of serotonin (5-HT) in the CNS. SNRIs have additional inhibitory activity at noradrenaline-reuptake sites. Different analytical methods for the routine monitoring and toxicological screening of SNRIs and SSRIs have been developed. Rapid quantification is a necessity for clinical use, allowing the possibility of diagnostics. This review focuses on recent advances of the methods that concern the determination of SSRIs and SNRIs in human biological samples. Sample preparation methodologies are discussed, because sample pretreatment is the most limiting and crucial step in analysis of biological matrices. Furthermore, information concerning the mechanism of action, side effects and toxicity are also given.