In the congestive heart failure state, autonomic dysregulation involves an increase in sympathetic tone and decrease in parasympathetic tone and is associated with increased mortality. It is possible that augmentation of the parasympathetic nervous system (PNS) with pharmacologic therapy may lead to improved symptoms and/or clinical outcomes. There are several new and established pharmacologic interventions that have been studied for their effect on the PNS, including antagonists of the renin-angiotensin system, beta-adrenergic antagonists, digoxin, and vasodilators. In this review, we discuss the current status of the published literature on pharmacologic influences on the PNS by both conventional and experimental drugs targeting heart failure as well as drugs that more directly influence vagal tone. While these analyses have been largely limited to putative surrogates for clinical outcomes like heart rate variability, and it is often difficult to differentiate between indirect and direct pharmacologic effects on the PNS, significant insight into potential mechanisms of action can be derived. The future evaluation of drugs in development for heart failure treatment should include a careful, scientifically sound exploration of the potential impact of the intervention on PNS activity.