Improvements in the medical therapy for chronic heart failure have led to a dramatic decrease in the morbidity and mortality of patients with heart failure over the past two decades. This improvement has been gained at the expense of an increasing number of potent drugs that heart failure patients have to take chronically. Because heart failure forms the end-stage of different cardiovascular diseases and their predisposing risk factors, patients need drug treatment not only for heart failure itself but also for related conditions. Even more, because most heart failure patients are elderly, a number of unrelated, noncardiovascular diseases become apparent, which further increase the number of pharmaceutical substances with which heart failure patients are treated. The resulting polypharmacy leads to problems including economic burden, patient compliance, and most importantly, partly unpredictable drug interactions. This article reviews the existing data concerning some of these problems, to provide an aid for choosing the appropriate drugs in heart failure patients and minimizing the patient's risk.