Recent years have witnessed a remarkable growth in literature related to the biology and treatment of multiple sclerosis (MS). The focus of this article is on aspects of the human immune response that have been implicated in the MS disease process and, as a corollary, represent rational targets for the development of safe and effective therapies. Much of the thinking about immune pathophysiology in patients with MS has been shaped by studies in animal models of central nervous system (CNS) inflammation. Translation to the human disease has continued to pose challenges. A simplified model of MS immune pathophysiology is presented to illustrate the basic principles by which peripheral immune activation, as well as compartmentalized immune responses within the CNS, is likely to impact the disease process and to identify the putative sites of action of current and future MS treatments.