The etiology of sterile inflammatory conditions is complex and affected by a variety of genetic, environmental and stochastic factors. But despite this overt complexity, progress has been made in elucidating mechanisms underlying disease pathogenesis. An intriguing new finding that has emerged over the past years was the realization that innate immune receptors participate in driving or aggravating disease manifestation. Originally identified as sensors of pathogens and as initiators of antimicrobial immune responses, receptors of the innate immune system recognize a variety of highly conserved microbe associated molecular patterns (MAMPs), including nucleic acids (NAs). While the sensing of DNA and RNA enables detection of a broad range of pathogens this strategy comes at a cost. Indeed, the capacity of NAs to accidentally activate innate sensors significantly contributes to inappropriate responses to self. In this review we will discuss recent findings based on established disease models.