Although often encoding fewer than a dozen genes, RNA viruses can overcome host antiviral responses and wreak havoc on the cells they infect. Some manage to evade host antiviral defences, whereas others elicit an aberrant or disproportional immune response. Both scenarios can result in the disruption of intracellular signalling pathways and significant pathology in the host. Systems-biology approaches are increasingly being used to study the processes of viral triggering and regulation of host immune responses. By providing a global and integrated view of cellular events, these approaches are beginning to unravel some of the complexities of virus-host interactions and provide new insights into how RNA viruses cause disease.