BACKGROUND: Heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD) are commonly occurring and interlinked conditions. Approximately 25%-40% of patients with HF have DM, and approximately 40%-50% of patients with HF have CKD. Both DM and CKD are associated with increased risk of incident HF. Furthermore, 40% of people with DM develop CKD, making DM the leading cause of kidney failure globally. Importantly, 16% of patients with HF have both comorbid DM and CKD, and the combination of these 3 comorbidities is associated with substantially increased risk for hospitalization and mortality. Mechanisms that underlie the relationships between HF, DM, and CKD are complex but likely relate to shared cardiovascular and metabolic risk factors, as well as downstream effects on inflammation, oxidative stress, and neurohormonal pathways. SUMMARY: This review outlines the epidemiology and links between HF, DM, and CKD, as well as current clinical evidence for the treatment of individuals with a combination of these comorbidities. A case study of a patient with concomitant HF, DM, and CKD is discussed to explore potential treatment approaches for patients in whom all 3 comorbidities exist. KEY MESSAGES: Treatment plans for patients with a combination of these 3 comorbidities should consider the available clinical evidence.