In patients with heart failure as a result of mechanical and neurohormonal derangements, macrophages secrete galectin-3, which is a paracrine and endocrine factor that stimulates additional macrophages, pericytes, myofibroblasts, and fibroblasts to proliferate and secrete procollagen I, which is irreversibly crosslinked to form fibrotic collagen. Normal plasma concentrations of galectin-3 are < 11.0 ng/mL. Galectin-3 measured in blood has been shown to predict the development of all-cause mortality and heart failure in the general population, identify increased risk for de novo heart failure and progressive loss of renal filtration function in healthy middle-aged adults, predict cardiac failure in patients after acute coronary syndromes, help establish the diagnosis of heart failure with preserved ejection fraction in patients presenting with effort intolerance, and aid in the prognosis of both systolic and nonsystolic heart failure for the outcomes of hospitalization and death. This article presents case discussions of these applications to highlight the importance of galectin-3 measurement across the spectrum of patients at risk for cardiorenal disease.