Two main etiological components are considered important in human autoimmune diseases including multiple sclerosis (MS), first the immunogenetic background and second environmental factors. Among the latter, infectious organisms are probably the most relevant, and epidemiological studies in MS firmly support that viral infections often precede disease exacerbations or the onset of MS. Infectious agents can contribute to disease development or phenotypic expression in different ways. Our focus will be directed on molecular mimicry, i.e. antigenic similarity between structural epitopes or peptide sequences from infectious organisms with those found in self proteins of the host. The intriguing concept of molecular mimicry has evolved substantially since its introduction over 20 years ago. We will summarize the most important developments and discuss puzzling questions, which remain open despite many claims that molecular mimicry is involved in the development of human autoimmune disease after infections or vaccinations.