Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat depression and a broad range of other comorbidities. The increased use of SSRIs in patients with various comorbidities treated with different drugs engenders the risk of pharmacokinetic drug interactions via cytochrome P450 (CYP450) enzymes inhibition. In the present review, we provide an overview of documented clinically significant drug interactions between SSRIs and other drugs co-prescribed in psychiatric patients for the same or other diseases. We further discuss the significance of drug interactions in the era of pharmacogenomics to underline the need for using information on both genotype and drug interactions towards implementing better clinical outcomes through personalized medicine.