The cardiovascular-kidney-metabolic syndrome (CKM) is characterized by the complex interaction between metabolic, cardiovascular, and renal disorders driven by interacting risk factors such as obesity, insulin resistance (IR), dysglycemia, atherogenic/metabolic dyslipidemia, and hypertension. These factors and common pathogenic mechanisms create a cycle of dysfunction in which the presence of one condition substantially increases the negative impact on the others. The relationships between the components of the metabolic syndrome, atherosclerotic cardiovascular disease, and chronic kidney disease are causal and mutually influencing. This conceptual definition of CKM should not be confused with the tools/criteria proposed to diagnose it. Although visceral obesity is considered the central element in this constellation of maladaptive, aggregated risk factors, it is not fully established whether this can be attributed to excess adipose tissue or to associated metabolic disorders. Risk factors and pathogenic mechanisms create a vicious circle without being able to specify whether they are cumulative, additive, or synergistic. Excess adipose tissue (visceral, dysfunctional) is a generator of subclinical inflammation, decreased adiponectin, increased adipokines and leptin, IR, and oxidative stress, which, together with the activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS), leads to endothelial dysfunction (reduced NO bioavailability, impaired relaxation) and maladaptive changes in the heart (diastolic dysfunction → decreased systolic function) and kidneys (hyperfiltration, Na + retention, glomerular sclerosis, tubulointerstitial fibrosis, proteinuria, decreased GFR). Hemodynamic changes, abnormal lipid metabolism, and hormonal response disorders constitute the main pathogenic links of cardiac and renal damage in obesity and potentiate heart–kidney interactions. Increased IR in individuals with obesity leads to increased lipolysis, free fatty acid abundance, inhibition of phosphatidylinositol-3-OH kinase (PI3K) signaling, hyperglycemia, and endothelial dysfunction. Hyperinsulinemia (secondary to IR) increases insulin-like growth factor 1 (IGF-1) synthesis with connective tissue development and fibrosis. We can conclude that CKM syndrome is a systemic disorder, a cluster of metabolic and vascular disorders (acceleration of atherosclerosis at the cardiac and renal levels) produced by neurohornal activation and inflammatory, hemodynamic and fibrotic processes, which combined create a risk profile, multiorgan dysfunction with a significant impact on morbidity and mortality.