Cardiovascular-kidney-metabolic (CKM) syndrome represents an umbrella term used for increasing awareness about the complex interplay between cardiovascular, renal, and metabolic systems, where dysfunction in one organ potentiates deterioration in others, significantly increasing the risk of heart disease. This chapter explores the pathophysiological mechanisms linking heart disease with common CKM comorbidities—type 2 diabetes, obesity, and chronic kidney disease. In this milieu of metabolic derangements, systemic inflammation and endothelial dysfunction play central roles. Obesity exacerbates heart failure through adipose-driven inflammation, insulin resistance, and adverse cardiac remodeling, while the bidirectional relationship between heart failure and type 2 diabetes involves neurohormonal activation, hepatic dysfunction, and impaired glucose metabolism. Additionally, the mutual reinforcement of renal and cardiac decline via hemodynamic stress and neurohormonal dysregulation highlights the close bidirectional relationship between these two systems, both in an acute and in a chronic setting, known as cardiorenal syndrome. Management of CKM syndrome requires a comprehensive, patient-centered approach adapted to individual risk estimation. Nonpharmacological strategies, such as increased physical activity, dietary modification, sodium and alcohol restriction, smoking cessation, weight optimization, and improved sleep quality, form the foundation of care. Pharmacological therapy should combine established agents, including RAAS inhibitors and lipid-lowering drugs, with novel agents supported by robust clinical trial data. GLP-1 receptor agonists and the dual GLP-1/GIP agonist tirzepatide have demonstrated cardiovascular and renal benefits, while SGLT2 inhibitors provide substantial prognostic improvement in heart failure and chronic kidney disease, regardless of glycemic status. Additionally, finerenone—a nonsteroidal mineralocorticoid receptor antagonist—has shown promise in diabetic CKD and emerging efficacy in HFpEF and HFmrEF, though further guideline integration is pending.