Vaccinia virus (VACV), a prototype member of the poxvirus family, has been used from the early times after interferons (IFN) were discovered, as a model virus cell system to analyze the mode of action of IFN. This large DNA-containing virus (around 200 kb) replicates entirely in the cytoplasm of the cell, taking rapidly over the host cell machinery for virus multiplication. In the presence of IFN, this virus exhibits sensitivity or resistance depending on the virus–host model. With the discovery of IFN-induced enzymes, the sensitivity of VACV to IFN was correlated with dsRNA activation of the protein kinase PKR and 2′–5′-OAS/RNaseL systems leading to a translational block by the phosphorylation of the eIF2α factor and RNA breakdown. Following sequencing of the VACV genome and generation of deletion mutants, the resistance phenomenon to IFN was shown to be exerted through inhibition of multiple pathways. This review analyzes current knowledge on the VACV genes encoding proteins acting as decoy receptors to block the activity of type I and type II IFNs, targeting cytokines and chemokines, and antagonizing intracellular signaling pathways (pattern recognition receptors [PRRs] signaling). The molecular dissection of how VACV prevents the IFN response is providing important insights on our understanding of antiviral action and immune surveillance.