The remarkable capacity of the mammalian immune system to coordinate deadly attacks against numerous invading pathogens, yet turn a blind eye to self-tissues continues to fascinate immunologists. It has been clear for some time that immune cells capable of recognizing self-proteins exist in normal individuals without seemingly causing harm. The 'peripheral tolerance' mechanisms that keep these cells in check are the focus of intense research, not least because defects in these pathways might cause autoimmune diseases. In this review, new developments in our understanding of peripheral tolerance are discussed.