Programmed Ribosomal Frameshifting (PRF) is a mechanism that alters the mRNA reading frame during translation, resulting in the production of out-of-frame proteins. PRF plays crucial roles in maintaining cellular homeostasis and contributes significantly to disease pathogenesis, particularly in viral infections. Notably, PRF can induce immune responses in the SARS-CoV-2 mRNA vaccine, further extending its biological significance. These multiple aspects of PRF highlight its potential as a therapeutic target. Since PRF efficiency can be modulated by cellular factors, its expression or silencing is context-dependent. Therefore, a deeper understanding of PRF is essential for harnessing its therapeutic potential. This review explores PRF biological significance in disease and homeostasis. Such knowledge would serve as a foundation to advance therapeutic strategies targeting PRF modulation, especially in viral infections and vaccine development.