Sympathovagal imbalance contributes to progressive worsening of heart failure (HF) and is associated with untoward clinical outcomes. Based on compelling pre-clinical studies that supported the role of autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord stimulation, vagus nerve stimulation, and baroreceptor activation therapy in patients with HF with a reduced ejection fraction. Whereas the phase II studies with baroreceptor activation therapy remain encouraging, the larger clinical studies with spinal cord stimulation and vagus nerve stimulation have yielded disappointing results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation in the failing heart, as well provide a critical review of the recent clinical trials that have sought to modulate autonomic tone in HF patients. This review will conclude with an analysis of some of the difficulties in translating device-based modulation of the autonomic nervous system from pre-clinical models into successful clinical trials, as well as provide suggestions for how to move the field of neuromodulation forward.