The immunoproteasome is a specific proteasome isoform induced by interferons. Its proteolytic function has been almost exclusively connected with the adaptive immune response and improved MHC class I antigen presentation. However, IFN-signaling also exposes cells to oxidative stress with concomitant production of nascent-oxidant damaged poly-ubiquitylated proteins. Here we discuss how immunoproteasomes protect cells against accumulation of toxic protein-aggregates and how i-proteasomes dysfunction associates with different diseases. We propose that the immunoproteasome has a central function at the interface between the innate and adaptive immune response and that its predominant protective innate function determines its favorable role in the adaptive immune response.