Autophagy constitutes a major catabolic process for the quality control of internal proteins and organelles of eukaryotic cells, and is emerging as an essential part of the host antiviral defense. Many studies have shed light on the importance of autophagy in homeostasis, but it is not well understood how viruses co-opt the cellular autophagic pathway to establish virulence in vivo. Our recent study presents direct in vivo evidence for the key role of the anti-autophagic aspect of the virally encoded Bcl-2 proteins in the chronic infection of oncogenic gamma-herpesviruses and proposes that cellular autophagy may have a substantial effect on viral persistence and may influence the in vivo fitness of viruses. This discovery expands upon known antiviral activities of the autophagy machinery and also suggests new approaches for treating some virally induced diseases.