The heart and the kidneys are closely interconnected, and disease in one organ system can lead to disease in the other. This interdependence is illustrated in heart failure with reduced ejection fraction (HFrEF), where worsening heart failure (HF) can lead to renal dysfunction and vice versa. Further complicating this situation is the fact that drugs that serve as guideline-directed medical therapy for HFrEF can affect renal function. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of medication with an evolving role in HF and chronic kidney disease (CKD). Initially found to have benefits in diabetic patients, new research established potential cardiovascular and renal benefits in patients with HF independent of their diabetic status and in populations with CKD. This has been established by landmark trials such as EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction), EMPA-TROPISM (Are the 'Cardiac Benefits' of Empagliflozin Independent of Its Hypoglycemic Activity), CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), and DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction). Multiple mechanisms responsible for these benefits have been suggested by clinical and non-clinical studies, and involve cardiac and renal energetic efficiency, cardiac remodelling, preservation of renal function, immunomodulation, changes in haematocrit, and control of risk factors. As such, SGLT2 inhibitors have tremendous potential to improve outcomes in populations with HF and CKD. The purpose of this review is to discuss the current evidence and underlying mechanisms for the cardio-renal benefits of SGLT2 inhibitors in patients with HFrEF. © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.