Despite a general awareness of the problem of drug interactions and widespread efforts to monitor them, the physician fraternity has failed so far in predicting and preventing them. Because drug interactions could not be generally predicted, one had to wait till they appeared in literature. Drug interactions are complex and chiefly unpredictable as a known interaction may not occur in every individual taking the drug or even a drug in the same class. Most of the drug interactions occur on long term use of drugs and are difficult to predict. This article highlighted the dangerous drug interactions occur on long term care, their impact, mechanism, management and prevention. Understanding these potential reactions and their mechanisms help us to navigate the hazardous waters of combining drugs on long term care.