Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.