Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the transcription of cells. Due to characteristics like rapid induction and signaling, IFNs represent prototypic model systems for various aspects of biomedical research. In respect to the signaling and activated promoters, IFNs can be subdivided in two groups. Here, alterations of the cellular proteome of human cells treated with IFN and IFN were elucidated in a time-dependent manner by mass spectrometry-based quantitative proteome analysis. The majority of protein regulations were strongly IFN type- and time-dependent. In addition to the expected upregulation of IFN-induced proteins, an astonishing number of proteins become profoundly repressed especially by IFN. Taken together, our comprehensive analysis deciphers the human interferome and its kinetics of protein induction and repression.