In personalized medicine, the appropriate drugs for an individual patient are selected based on the patient’s medical history, diagnostic testing, and genetic information for the purpose of minimizing drug interactions (DIs), side effects, and adverse drug reactions (ADRs) and to obtain the maximum therapeutic benefit. The DI is one of the major problems of pharmacotherapy, which perhaps leads to adverse outcome or therapeutic failure if not properly addressed. In clinical practice, patient safety is likely to improve through the identification of frequently occurring DIs by pharmacist and notifying the other members of the health-care team. Recently, a software was introduced, which detects DIs with good precision; however, this software requires a constant update. Health-care professionals require adequate knowledge and skills on how to identify and avoid DIs to enable them complement the software assessment. Basically, DIs include drug–drug, drug–food, drug–herbal, and drug–disease interactions. These possibilities can be identified from chemical properties, pharmacokinetics, and pharmacodynamics of the drug, patient medical history, concomitant disease, or organ failure. Focusing on DIs will help to reduce drug-related problems, advance the evidence-based medicine, and improve the level of patient satisfaction. Adequate knowledge of drug DIs will enable the health-care professionals to individualize the patient treatment in order to get maximum therapeutic benefit. This script is aimed at describing the various classes of DIs, their causes, and their implications in clinical practice and personalized medicine.