Toll-like receptors (TLRs) and the receptors for interleukin (IL)-1, IL-18 and IL-33 are required for defence against microbial pathogens but, if hyper-activated or not switched off efficiently, can cause tissue damage and inflammatory and autoimmune diseases. Understanding how the checks and balances in the system are integrated to fight infection without the network operating out of control will be crucial for the development of improved drugs to treat these diseases in the future. In this Cell Science at a Glance article and the accompanying poster, I provide a brief overview of how one of these intricate networks is controlled by the interplay of protein phosphorylation and protein ubiquitylation events, and the mechanisms in myeloid cells that restrict and terminate its activation to prevent inflammatory and autoimmune diseases. Finally, I suggest a few protein kinases that have been neglected as drug targets, but whose therapeutic potential should be explored in the light of recent advances in our understanding of their roles in the innate immune system.