We have recently shown that a third of reliably-inferred alternative mRNA isoforms are candidates for nonsense-mediated mRNA decay (NMD), an mRNA surveillance system (Lewis et al., 2003, PROC: Natl Acad. Sci. USA, 100, 189-192). Rather than being translated to yield protein, these transcripts are expected to be degraded and may be subject to regulated unproductive splicing and translation (RUST). Our initial experimental studies are consistent with these predictions and suggest an unappreciated role for NMD in several human diseases.