Cardiorenal syndrome (CRS) represents a complex clinical condition characterized by bidirectional interactions between cardiac and renal dysfunction, in which therapeutic interventions targeting one organ may substantially influence the function of the other. Effective management of CRS requires an integrated, physiology-driven approach that balances hemodynamic optimization, decongestion, and long-term neurohormonal modulation while accounting for altered pharmacokinetics and pharmacodynamics in chronic kidney disease. Contemporary understanding emphasizes venous congestion, maladaptive neurohormonal activation, inflammation, and metabolic dysregulation as central mechanisms driving disease progression. This chapter reviews evidence-based therapeutic adjustments across acute and chronic CRS, with particular focus on diuretic strategies, sequential nephron blockade, and emerging metabolic therapies. Loop diuretics remain the cornerstone of acute decongestion, but diuretic resistance frequently necessitates adjunctive distal or proximal tubular blockade, including thiazide-like agents, acetazolamide, and sodium–glucose cotransporter-2 inhibitors. In chronic CRS, disease-modifying therapies—such as renin–angiotensin–aldosterone system inhibitors, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and incretin-based agents—play a pivotal role in slowing structural deterioration in both organs. Individualized dosing, vigilant monitoring for renal dysfunction and electrolyte disturbances, and prioritization of integrated physiologic improvement over isolated laboratory changes are essential. An integrated therapeutic framework is critical to improving outcomes in this high-risk population.