Viral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe and even life-threatening diseases. Such varied infection outcome applies also to the newly emerged SARS-CoV-2, the cause of COVID-19. While the correlates of severe disease have been explored for various infections, the pathophysiology that differentiates symptomatic from asymptomatic infection remains ill understood. We recently identified the molecular underpinnings of symptomatic infection, using the live attenuated yellow fever virus vaccine (YF17D) as a model. Using whole blood transcriptomic and metabolomic profiling, we found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid (TCA) cycle activity at baseline showed increased susceptibility to symptomatic outcome. Like most viral infections, YF17D infection induced translational and metabolic activities necessary, at least in part, to reproduce new viruses. Such increased activities exacerbated ER stress. The ensuing maladaptive ER stress response triggered downstream pro-inflammatory responses that cascaded into symptomatic outcome. Our findings thus suggest that ER stress response and immunometabolism underpin symptomatic yellow fever; similar processes could also extend to other viral infections, including COVID-19. I will summarize these findings and suggest how antiviral approaches could be applied to prevent disease development and progression.