Myocardial dysfunction and heart failure (HF), frequently described as cardiotoxicity, are the most concerning cardiovascular complications of cancer therapies, causing an increase in morbidity and mortality, even due to early discontinuation of antineoplastic drugs. Research efforts have been done to prevent and treat this phenomenon, in particular through early administration of drugs inducing renin-angiotensin-aldosterone system blockade. Sacubitril/valsartan, a combination of an angiotensin receptor blocker and a neprilysin inhibitor pro-drug, has recently represented a game changer in the scenario of treatment of HF with reduced ejection fraction. However, patients with HF induced by cancer therapy were a priori excluded from the approval study. Therefore, safety and efficacy of this drug in this special population require further investigation. Available evidence, even though only derived from case reports or observational studies, seems to confirm the promising role of this new pharmacological strategy, paving the way for the use of sacubitril/valsartan in cardio-oncology. Prevention and treatment of HF in these highly vulnerable patients is a special need to allow full oncologic treatment and improve overall survival, highlighting the need for ad hoc prospective studies.