The sympathetic branch of the autonomic nervous system is indispensable in maintaining overall health of the body with major roles in regulating functions of all the major organ systems. However, several basic and clinical science studies over the past several decades have clearly established that chronic overactivity of the sympathetic nervous system (SNS) initiates and propagates cardiometabolic and immunologic disorders potentiating increased morbidity and mortality. While the influence of elevated SNS tone to damage the cardiovascular system and precipitate cardiovascular disease is generally well known, its adverse influences on fuel metabolism are less well appreciated. Respecting the influence of elevated SNS tone in metabolic control, multiple clinical studies indicate that elevated SNS tone is among the earliest physiological perturbations that predicts and potentiates future insulin resistance and subsequent type 2 diabetes. Such SNS overactivation induces increases in hepatic glucose production, inhibition in post-meal hepatic glucose disposal, increased free fatty acid mobilization from adipose tissue, increased liver triglyceride synthesis, increased reactive oxygen species generation and inflammation in adipose and liver (and the vasculature, heart, and kidney) and insulin resistance – all pathophysiological events driving insulin resistance syndrome (see figure and reference list). Worse yet, these metabolic perturbations of elevated SNS tone (e.g., elevated plasma free fatty acid levels) feedback centrally to further stimulate central nervous system activation of SNS tone thus trapping the individual in a chronic state of neurometabolic dysregulation of SNS overdrive and subsequent cardiometabolic disease. In coming newsletters we will discuss the clinical evidence that dopamine agonism functions as a sympatholytic agent.