Cardiovascular-kidney-metabolic (CKM) syndrome represents a progressive condition caused by biological, social, and environmental factors, inducing an excess and dysfunctional adipose tissue. This systemic disorder involves complex interactions among metabolic syndrome (MetS), chronic kidney disease (CKD), and cardiovascular disease (CVD), and evolves through distinct clinical stages, from asymptomatic risk states to advanced multiorgan dysfunction. The pathophysiology includes chronic inflammation, oxidative stress, insulin resistance, and neurohormonal mechanisms such as RAAS activation. The American Heart Association (AHA) has proposed a five-stage model for CKM syndrome (stages 0–4), aligned with heart failure (HF) progression, emphasizing the importance of early detection and intervention. Management strategies include lifestyle modifications, pharmacological therapies, and multidisciplinary care. An effective approach to CKM syndrome involves addressing comorbid conditions such as diabetes, obesity, atrial fibrillation, and CKD, using evidence-based strategies, including SGLT2 inhibitors, GLP-1 receptor agonists, statins, and anticoagulants. Preventive measures, consisting of the AHA’s “Life’s Essential 8” and the PREVENT risk prediction equations, are critical for reducing disease burden. This chapter highlights the interconnected processes of CKM syndrome and offers guidance on prevention, risk assessment, and treatment strategies to optimize patient outcomes.