Pharmacotherapy becomes increasingly complex and therapeutic targets are more and more ambitious for both care and prevention. Therefore, polypharmacy is frequent, which exposes the patient to a high risk of drug-drug interactions. These are often underestimated although they are responsible for many adverse events that may be serious and even fatal. In the present paper, we will first briefly recall the main cautions in the use of medications as well as the most common conditions favouring the occurrence of harmful drug interactions. Then, we will analyze the various mechanisms leading to drug interactions, emphasizing especially those involving cytochrome P450 enzymatic system and P-glycoprotein. Finally, we will illustrate these theoretical considerations with some examples of drug interactions, among the most dangerous and the most frequent in clinical practice.