: The Prospective Comparison of Angiotensin Receptor Antagonist and Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) has shown a reduction in the risk of death and heart failure hospitalizations with sacubitril/valsartan, compared with enalapril, in patients with heart failure and reduced ejection fraction. Guidelines now recommend the substitution of angiotensin-converting enzyme inhibitors or AT1 blockers with sacubitril/valsartan in patients with heart failure and reduced ejection fraction. The aim of this review is to discuss factors that may have an impact on the implementation of these guidelines into clinical practice. The main limitation is that, based on the inclusion criteria of PARADIGM-HF, sacubitril/valsartan is not indicated in patients with heart failure and preserved ejection fraction, although they may be the majority of the patients with heart failure. The trial enrolled ambulatory patients and thus start of sacubitril/valsartan is not indicated in those hospitalized for heart failure. A drug's tolerability may be limited by hypotension with, however, a lower rate of renal dysfunction, compared with enalapril. The cost of the new treatment is also an issue. Similarly to what occurred when other neurohormonal antagonists have been introduced in clinical practice, increased awareness of poor heart failure outcomes and better patients' management programs may be of utmost importance for the implementation of this new agent.