The spectrum of sepsis and septic shock remains a highly prevalent disease state, carrying a high risk of morbidity and mortality. The sympathetic nervous system (SNS) plays an important role in this initial cascade, enabling the host to respond to invading pathogens; however, prolonged activation can become pathological. The potential for unregulated sympathetic tone to become of detriment in patients with sepsis has fueled interest in the role and impact of sympatholysis, the selective inhibition of sympathetic tone. The cornerstone of septic shock therapy for decades has been the supplementation of catecholamines and thus potential further perpetuation of this sympathetic dysregulation. Although the theory of sympatholysis circulates around cardiovascular effects and stroke volume optimization, the impact of augmenting the SNS may extend well beyond this, including the impacts on the immune system, inflammatory cascade, and even gene transcription. Presently, the most robust clinical evidence involves the use of the cardioselective β-blocker esmolol in patients with septic shock with persistent tachycardia secondary to catecholamine use. Evidence is isolated only to animal models with α-agonists. Future evidence stands to elucidate the balance of sympathetic and autonomic tone as well as the potential role of redirecting and maximizing sympathetic activity.