Significant improvements in the morbidity and mortality associated with chronic heart failure have been gained with the use ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. However, the use of these agents is often limited by their propensity to precipitate worsening renal function and hyperkalemia, particularly in patients with chronic kidney disease. Several pharmacologic agents have been developed in recent years that utilize the gastrointestinal tract as an alternate route for drug absorption, electrolyte exchange, and drug and electrolyte elimination. The existing data establishing the safety and efficacy of these novel agents will be the focus of this review.