Heart Failure is the end result of a diverse set of causes such as genetic cardiomyopathies, coronary artery disease and hypertension and represents the primary cause of hospitalization in Europe. This serious clinical disorder is mostly associated with pathological remodeling of the myocardium, pump failure and sudden death. Whilst the survival of heart failure patients can be prolonged with conventional pharmacological therapies the prognosis remains poor. New therapeutic modalities are thus needed that will target the underlying causes and not only the symptoms of the disease. Under chronic cardiac stress, small non-coding RNAs, in particular microRNAs, act as critical regulators of cardiac tissue remodeling and represent a new class of therapeutic targets in patients suffering from heart failure. Here, we focus on the potential use of microRNA inhibitors as a new treatment paradigm for heart failure.Molecular Therapy (2015); doi:10.1038/mt.2015.133.