We have recently discovered a novel connection between the TNF-related apoptosis inducing ligand (TRAIL) cytokine system and CMV. TRAIL is a TNF-family cytokine that can bind to several receptors (TRAIL receptor- 1, 2 ,3 and 4), of which two (R1 and R2) encode a cytoplasmic “death domain” and can mediate apoptosis of transformed cells (death receptors, DR). We showed several years ago that human adenovirus encodes 3 proteins in the E3 region of its genome (10.4K/14.5K/6.7K) that specifically downregulate the TRAIL DRs from surface of infected cells, desensitizing them to TRAIL-mediated killing. Now, we have discovered that human CMV (HCMV) also inhibits expression of the TRAIL DRs, and uses the UL141 protein to accomplish this task. In turn, we have solved the three dimensional structure of the UL141/TRAIL-R2 complex by X-ray crystallography in collaboration with Dr. Zajonc’s group at LJI. More recently we have shown that mouse CMV (MCMV) also uses a specific strategy to inhibit the TRAIL-DR via use of m166, the first identified role for this viral protein. In the absence of m166, MCMV replication is highly compromised due to its inability to inhibit TRAIL signaling, showing the key importance viral inhibition of this immune pathway plays.