Venlafaxine (VEN) is an antidepressant agent widely used nowadays as an alternative to selective serotonin reuptake inhibitors (SSRIs), particularly for the treatment of SSRI-resistant depression. As the co-administration of antidepressant drugs with other medications is very common in clinical practice, the potential risk for pharmacokinetic and/or pharmacodynamic drug interactions that may be clinically meaningful increases. Bearing in mind that VEN has exhibited large variability in antidepressant response, besides the individual genetic background, several other factors may contribute to those variable clinical outcomes, such as the occurrence of significant drug-drug interactions. Indeed, the presence of drug interactions is possibly one of the major reasons for interindividual variability, and their anticipation should be considered in conjugation with other specific patients' characteristics to optimize the antidepressant therapy. Hence, a comprehensive overview of the pharmacokinetic- and pharmacodynamic-based drug interactions involving VEN is herein provided, particularly addressing their clinical relevance.