Computational methods identify alternate splice forms of known gene transcripts and isoforms that are subject to NMD (nonsense-mediated decay). These methods were used to identify thousands of human genes that generate alternative splice forms, and to demonstrate that about a third of these are subject to NMD. This high prevalence of NMD-targeted transcripts indicates a systemic way of regulating gene expression--by shunting gene expression to nonproductive splice variants. This endemic regulation is exploited to engineer regulation of gene expression, to characterize splice pathway components and to assay splice environments, for example, using NMD-regulated reporter genes.