Drug-drug interactions (DDIs) are still an important contributor to ineffective treatment or deleterious side effects. Therefore, assessing the prevalence and clinical relevance of frequently observed potential DDIs is an important step towards improving medication safety. We firstly explored the frequency of potentially interacting substrate and inhibitor of three main drug-metabolizing enzymes (CYP2D6, CYP2C19, CYP2C19) co-prescriptions in the Dutch population. We found that CYP2D6/2C19/2C9-mediated potential DDIs were frequent (1 to 2 per 100 users) despite the use of the DDI alerting systems. We then estimated the burden and impact of one of the most frequently combined interacting drugs, metoprolol (a CYP2D6 substrate) and paroxetine/fluoxetine (a CYP2D6 inhibitor), among a high-risk population of older persons. We observed that the burden of metoprolol-paroxetine/fluoxetine combinations is high among older Dutch inhabitants. After systematically reviewing all studies related to the clinical relevance of the interactions, we found conflicting findings but most studies concluded that the DDIs can lead to adverse clinical consequences. Furthermore, we investigated the influence of genetic polymorphism in the severity of DDIs. We presented that the severity of DDIs depends on the metabolic activity of drug-metabolizing enzymes. Even more, if a genetic polymorphism and an effector drug co-occur this may result in a complex drug-drug-gene interaction (DDGI) responsible for greater inter-individual variability in the magnitude of interaction than a DDI. Hence, the management of drug interactions in clinical practice should consider the genetic background of the patients to produce a more appropriate and personalized management of drug interaction.