The pathological features of multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system, support an autoimmune etiology. Strong evidence has been provided for a potential functional defect of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) in patients with relapsing-remitting MS. More recently, alterations in homeostatic parameters related to the development and function of naive and memory-like Tregs were discovered in MS patients. In this review, we evaluate the evidence for disturbed Treg homeostasis in MS and discuss the role of potential compensatory mechanisms in the chronic disease phase. Better insights into the processes underlying the compromised immune regulation in MS patients will be important to understand the potential of Treg-based therapies.