Induction of interferons during viral infection is mediated by cellular proteins that recognise viral nucleic acids. MDA5 is one such sensor of virus presence and is activated by RNA. MDA5 is required for immunity against several classes of viruses, including picornaviruses. Recent work showed that mutations in the IFIH1 gene, encoding MDA5, lead to interferon-driven autoinflammatory diseases. Together with observations made in cancer cells, this suggests that MDA5 detects cellular RNAs in addition to viral RNAs. It is therefore important to understand the properties of the RNAs which activate MDA5. New data indicate that RNA length and secondary structure are features sensed by MDA5. We review these developments and discuss how MDA5 strikes a balance between antiviral immunity and autoinflammation.