: Despite recent improvement in therapy, heart failure with reduced ejection fraction (HFrEF) remains a major cause of increased mortality and morbidity.We have reviewed recent advances in the medical treatment of the patients with HFrEF, including drugs introduced into clinical practice for the first time in the most recent guidelines and drugs undergoing active clinical research in major randomized trials. Sacubitril/valsartan for HFrEF treatment, empagliflozin for heart failure prevention in diabetic patients, ferric carboxymaltose for iron deficiency and potassium binders for hyperkalaemia belong to the first category, whereas drugs undergoing phase 3 clinical trials include omecamtiv mecarbil and vericiguat. A large trial with rivaroxaban has been recently concluded.In conclusion, new drugs recently introduced for HFrEF treatment need implementation in clinical practice, as well as further studies to possibly expand their indications. Ongoing trials will show the role of new drugs acting on cardiac and vascular function and new mechanisms potentially involved in HFrEF progression.