Cardio-renal syndromes represent a complex pathologic interaction between the heart and the kidney, in which the acute or chronic dysfunction of one organ contributes to the deterioration of the other. Beyond hemodynamic and neurohormonal mechanisms, metabolic dysfunctions play a key role in the progression of these syndromes and contribute to the development of a cardio-renal-metabolic vicious cycle in which metabolite accumulation, chronic inflammation, and dysregulation of mineral homeostasis amplify the deterioration of both organs. Understanding this interdependence between organs, in which the damage of one of them generates systemic metabolic disturbances which, in turn, affect, structurally and functionally, the other organ, and so on, has led to a change of paradigm: the main goal in treating these patients is not just to maintain the renal and cardiac function, but also to correct the metabolic dysfunction to break the vicious cycle. This chapter analyses, in detail, the components of metabolic dysfunction in CRS—specifically glycemic control, metabolic acidosis, dyslipidemia, and chronic kidney disease—and mineral and bone disorder, and identifies modern, personalized therapeutic strategies to improve the prognosis of these patients.