Abstract Neuromodulation, specifically spinal cord stimulation (SCS), relieves pain and improves organ function. This chapter discusses the limited information presently available about the underlying mechanisms that explain the beneficial effects of treating patients with SCS. Where applicable, information is presented about translational research that illustrates the importance of collaboration between clinicians, basic scientists, and engineers. This chapter presents the infant stage of studies that attempt to explain the mechanisms which come into play for treating neuropathic pain, ischemic pain in peripheral vascular disease, and diseases of the visceral organs, specifically the gastrointestinal tract and the heart. The basic science studies will demonstrate how SCS acts on various pain syndromes and diseases via multiple pathways in the central nervous system as well as in somatic structures and visceral organs.