Our immune system faces the intricate task of eliminating pathogenic microorganisms, while autoimmunity against self-components or intestinal flora must be prevented. This complex task demands an exceptional level of regulation and specificity. Hereto, immune cells are equipped with a myriad of surface receptors, including cytokine-receptors and pathogen recognition receptors. In this review we describe two important PRR families, Toll-like receptors and nucleotide-binding oligomerization domain leucine-rich repeat proteins, and their crucial role in instruction of the immune response. Interestingly, these key immune-receptors have recently been identified as major players in several immune disorders, such as systemic lupus erythematosus, Crohn’s disease, auto-inflammatory diseases and rheumatoid arthritis. These findings, and their implications for future research and therapy of immune disorders, will be discussed.