The 2'-5' oligoadenylate synthetases (OASs) are type I interferon-inducible enzymes that, with ribonuclease L (RNase L), have been studied in the context of their coupled action as antiviral effectors. RNase L degrades host and viral ssRNA, affecting diverse cellular processes including translational arrest, interferon response, and apoptosis, all of which are thought to restrict viral replication. Recent studies of recessive inborn errors of human OAS1, OAS2, and RNase L, however, revealed that for SARS-CoV-2 infection, the main protective action of this pathway in natura may be through restricting phagocyte-driven postviral inflammation rather than restricting early viral replication in the respiratory tract. This finding is consistent with the identification of gain-of-function OAS1 mutations in humans with autoinflammation also driven by myeloid cells. Here, we retrace the investigation of the OAS-RNase L pathway, focusing on these recent in natura studies in humans that reposition the pathway as a determinant of the inflammatory response under natural conditions of infection.