Ubiquitinating enzymes (UBEs) catalyze protein ubiquitination, a reversible process countered by deubiquitinating enzyme (DUB) action. Five DUB subfamilies are recognized, including the USP, UCH, OTU, MJD and JAMM enzymes. USP18 (also known as UBP43) is a deubiquitinase best known for catalyzing the removal of ISG15, an interferon-regulated ubibiquitin-like protein, from conjugated proteins. Removal of ISG15 from target proteins by the USP18 peptidase maintains the critical cellular balance of ISG15-conjugated proteins important for normal development and brain function. Following induction by IFN or LPS, USP18 binds the INF receptor subunit IFNAR2 and inhibits signal transduction through the JAK-STAT pathway. USP18 regulation of IFN signaling inhibits IFN-mediated apoptosis and does not necessarily rely on USP18 peptidase activity. As the therapeutic use of recombinant IFN can lead to refractory IFN signaling and a less effective response, the combination of IFN treatment and regulation of USP18 expression may produce a more positive outcome.