The interferon (IFN) family of cytokines regulates many cellular processes, such as transcription, translation, post-translational modifications, and protein degradation. IFNs induce growth inhibition and/or cell death, depending on the cell type, by employing different proteins. This review describes a novel growth-suppressive pathway employed by IFNs that affects rRNA levels. Maturation of rRNA involves numerous noncoding small regulatory RNA-guided processes. These regulatory RNAs, called small nucleolar RNA (snoRNAs), function as a ribonucleoprotein particle (RNP) in the nucleolus. The biogenesis of snoRNPs is dependent on core protein and assembly factors. Our laboratory recently isolated a growth-suppressive protein gene associated with retinoid-IFN-induced mortality (GRIM)-1 using a genetic screen. IFN-inducible GRIM-1 (SHQ1) is an assembly factor that controls one arm of the snoRNP machinery. GRIM-1 inhibits sno/scaRNP formation to induce growth suppression via reduction in mature rRNA levels. Loss of GRIM-1 observed in certain cancers implicates it to be a novel tumor suppressor. Certain snoRNAs have been reported to act as either oncogenes or tumor suppressors in vitro. Recent studies have shown that certain sno/scaRNAs are further processed into micro RNA-like molecules to control translation of protein-coding RNAs. We present a model as to how these small regulatory RNAs influence cell growth and a potential role for GRIM-1 in this process.