Although mobile genetic elements, or transposons, have played an important role in genome evolution, excess activity of mobile elements can have detrimental consequences. Already, the enhanced expression of transposons-derived nucleic acids can trigger autoimmune reactions that may result in severe autoinflammatory disorders. Thus, cells contain several layers of protective measures to restrict transposons and to sense the enhanced activity of these “intragenomic pathogens”. This review focuses on our current understanding of immunogenic patterns derived from the most active elements in humans, the retrotransposons long interspersed element (LINE)-1 and Alu. We describe the role of known pattern recognition receptors in nucleic acid sensing of LINE-1 and Alu and the possible consequences for autoimmune diseases.