Drug-drug interactions (DDIs) occur when one drug adds to or diminishes the effect of another drug (ie, pharmacodynamic interaction) or affects the absorption, distribution, metabolism, or excretion of another drug (ie, pharmacokinetic interaction). Such interactions cause 26% of all adverse drug events (ADEs) and are associated with a significant burden on the health care system through increased hospitalizations. Some of the most common DDIs result from alterations in drug metabolism through interactions with cytochrome P450 enzymes and absorption through interactions with P-glycoproteins. Other common DDIs occur because of additive effects, including combinations of drugs that increase the risk of seizures, prolong the QT interval, increase central nervous system depression, and increase the risk of serotonin syndrome. Drug-related clinical decision support has been shown to improve the quality of patient care and decrease ADE rates. However, alerts generated by such systems should be interpreted using clinical judgment to determine the risks and benefits of certain drugs on a patient-specific basis. Family physicians can prevent clinically significant DDIs and optimize drug safety by using drug interaction software, along with a general understanding of common DDI mechanisms and collaboration with pharmacists.