In 1985, John Monaco —the discoverer of LMP-2 and -7, the inducible components of the immunoproteasome— asked his advanced immunology class as to why the MHC region contained not only structural genes, but several others as well, whose functions were then unknown. As we drew a blank, he quipped: perchance because many of the MHC genes are induced by interferon-γ (IFN-γ)! The ensuing three decades have unveiled the profound fundamental and clinical implications of that classroom tête–à–tête. Amongst its multitudinous effects, IFN-γ induces genes enhancing antigen processing and presentation to T cells; such as those encoding cellular proteases and activators of proteases. In this issue, Keller et al. [Eur. J. Immunol. 2015. 45: pp—pp] demonstrate that the limited success of MART-1/Melan-A-targeted immunotherapy in melanoma patients could be due to inefficient MART-126—35 presentation, owing to the proteolytic activities of IFN-γ-inducible β2i/MECL-1, proteasome activator 28 (PA28), and endoplasmic reticulum-associated aminopeptidases-associated with antigen processing (ERAP-1). Specifically, whilst β2i and PA28 impede MART-126—35 liberation from its precursor protein, ERAP-1 degrades this epitope. Hence, critical to effective cancer immunotherapy is deep knowledge of T-cell-targeted tumour antigens and how cellular proteases generate protective epitope(s) from them, or destroy them.