The concept of heart failure has undergone several paradigm shifts in the past few decades. Therapeutic targets directed at the heart pump have shifted to circulatory haemodynamics to the current neurohormonal model. Consequently, therapeutic modalities have similarly evolved alongside clinical trials. Successive trials have tested newer drugs in addition to established therapies, resulting in evidence-based treatments necessitating polypharmacy. Optimal heart failure therapy has therefore become increasingly complex. It is only after understanding the precise modes of drug action, as well as the relevance of the design of clinical trials, will physicians hopefully be able to tailor the medical therapy optimally towards the individual patient with heart failure.