Abstract Like most basic molecular mechanisms, programmed -1 ribosomal frameshifting (-1 PRF) was first identified in viruses. Early observations that global dysregulation of -1 PRF had deleterious effects on yeast cell growth suggested that -1 PRF may be used to control cellular gene expression, and the cell cycle in particular. Collection of sufficient numbers of viral -1 PRF signals coupled with advances in computer sciences enabled 2 complementary computational approaches to identify -1 PRF signals in free living organisms. The unexpected observation that almost all -1 PRF events on eukaryotic mRNAs direct ribosomes to premature termination codons engendered the hypothesis that -1 PRF signals post-transcriptionally regulate gene expression by functioning as mRNA destabilizing elements. Emerging research suggests that some human diseases are associated with global defects in -1 PRF. The recent discovery of -1 PRF signal-specific trans-acting regulators may provide insight into novel therapeutic strategies aimed at treating diseases caused by changes in gene expression patterns.