Pattern recognition receptors (PRRs), expressed on cells of both the innate and adaptive immune systems, serve as sentinels, waiting to alert the host to the first signs of microbial infection and to activate the initial line of immune defense. Research has increasingly demonstrated that many of the same PRRs also recognize self-epitopes that either are released from dying or damaged cells or are present at the surface of apoptotic cells or apoptotic bodies. In this context, PRRs play a critical role in tissue repair and the clearance of cellular debris. However, failure to appropriately regulate self-responses triggered by certain PRRs can have serious pathological consequences. The Toll-like receptor (TLR) gene family represents a case in point. TLR7, 8, and 9 were originally identified as receptors specific for bacterial and viral RNA and DNA, but more recent in vitro and in vivo studies have now linked these receptors to the detection of host RNA, DNA, and RNA- or DNA-associated proteins. In this context, they likely play a key role in the development of systemic autoimmune diseases.