Most antiviral therapies are pathogen-specific and likely to select for resistance if the virus can mutate the drug target. Rider et al. couple the ability to detect long double-stranded RNA (dsRNA)—a telltale indicator of viral infection in mammalian cells—with procaspase-activated apoptosis for broad-spectrum antiviral activity. Dubbed DRACOs (double-stranded RNA–activated caspase oligomerizers), these chimeric constructs each comprise (i) a terminal transduction domain for cell penetration, (ii) a dsRNA-binding domain to detect viral infection and (iii) an apoptosis-promoting domain, such as a procaspase-binding domain or a procaspase, which is activated by dsRNA-dependent oligomerization. When tested in 11 mammalian cell types, DRACOs are effective against 15 different viruses. Prophylactic intraperitoneal delivery of DRACOs also reduces the morbidity of mice following subsequent intranasal challenge with H1N1 influenza virus. The strategy seems best suited to situations when exposure to a dangerous virus is anticipated; in contrast, once an infection is established, the treatment may result in potentially dangerous inflammation and organ damage. Unfortunately, the earliest stages of viral infection are usually the most difficult to diagnose. Systemic delivery of DRACOs might also result in nondiscriminate killing of healthy cells infected with nonpathogenic viruses. (PLoS One 6, e22572, 2011)