Immunoglobulins with germline sequences occur in invertebrates and vertebrates and are named 'natural antibodies' (NAbs). They may target foreign antigens, self- or altered self-components and are part of the normal immunoglobulin repertoire. NAbs can act as systemic surveillance molecules, which tag damaged or stressed cells, invading pathogens and toxic protein aggregates for elimination by the immune system. Certain NAbs actively signal in different cell types with a broad range of responses from induction of apoptosis in cancer cells, stimulation of remyelination in glial cells and blocking disease propagation in neurodegenerative disorders. This lecture note emphasizes the different functions and characteristics of NAbs and their use as potential therapeutics in multiple sclerosis (MS) as an example for neuroinflammatory diseases. Within neurodegenerative diseases we will focus on Alzheimer's disease as the best investigated disease for immunotherapeutic approaches. We will highlight the role of the blood brain barrier (BBB) as the major obstacle for antibody based therapies of CNS diseases and stress on some novel approaches to lower the hurdle.