Gender-related issues in multiple sclerosis include the important and widely accepted clinical observations that men are less susceptible to the disease than women and also that disease activity in multiple sclerosis is decreased during late pregnancy. This article reviews mechanisms underlying each of these clinical observations and discusses the role of sex hormones in each. Specifically, the protective role of testosterone in young men and the protective role of the pregnancy hormone estriol in pregnant women are discussed. Rationale for novel therapies in multiple sclerosis based on the protective roles of these sex hormones is presented.