Background: The sodium-glucose co-transporter-2 (SGLT2) inhibitors were developed as glucose-lowering drugs to treat type 2 diabetes (T2D). However, significant reductions in clinical outcomes have now been demonstrated in patients with heart failure with reduced ejection fraction (HFrEF), irrespective of the presence of T2D. Multiple hypotheses have been proposed for the underlying mechanisms, and the data to support these proposals are emerging. Objectives: To review the clinical outcome data with SGLT2 inhibitors in HFrEF and the data to support the mechanisms for these clinical effects. Methods: Literature review was supported by a PubMed search for relevant articles up to 19 April 2022. Findings: Current data support increased diuresis and reverse cardiac remodelling as important mechanisms for the reductions in heart failure hospitalizations and mortality observed with SGLT2 inhibitors (empagliflozin or dapagliflozin) in patients with HFrEF. Alteration in intrarenal haemodynamic is likely contributing to the observed renoprotective effect of SGLT2 inhibitors. Conclusions: Solid clinical data support the current recommendations to use empagliflozin or dapagliflozin in HFrEF. The underlying mechanisms likely include changes in cardiac and intrarenal haemodynamic. Yet, these mechanisms do not seem to solely explain the observed magnitude of clinical effect with SGLT2 inhibitors in HFrEF, and other mechanisms may contribute.