PURPOSE OF REVIEW: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have taken centre stage in research and therapeutic efforts to modulate hard clinical outcomes in patients with heightened cardiovascular and renal risk profiles. Sympathetic nervous system (SNS) activation is a prominent feature across several cardiovascular and renal disease states. This review reflects on the remarkable clinical impact of SGLT2 inhibitors on cardiorenal outcomes, and navigates the evidence for a proposed clinically relevant interaction between SGLT2 and the SNS. RECENT FINDINGS: SGLT2 inhibitors exert several pleiotropic effects beyond glucose-lowering. These include, but are not limited to, diuresis and natriuresis, blood pressure lowering, reduction in inflammation and oxidative stress, stimulation of erythropoiesis, and improvement in cardiac energetics. Treatment with SGLT2 inhibitors is associated with significant improvement in cardiorenal outcomes irrespective of diabetes status. In addition, evidence from preclinical studies points to a strong signal of a bidirectional temporal association between SGLT2 inhibition and reduction in SNS activation. SUMMARY: Ongoing preclinical and clinical trials aimed at unravelling the proposed interaction between SGLT and SNS will enhance our understanding of their individual and/or collective contributions to cardiovascular disease progression and guide future targeted therapeutic interventions.