Alternative splicing (AS) strongly affects gene expression by generating protein isoform diversity. However, up to one-third of human AS events create a premature termination codon that would cause the resulting mRNA to be degraded by nonsense-mediated mRNA decay (NMD). The extent to which such events represent functionally selected post-transcriptional gene control, as opposed to noise in the splicing process, has been a contentious issue. Recent analyses indicate that many splicing regulatory proteins are themselves regulated by AS-NMD. Intriguingly, many of these AS-NMD events are coincident with ultraconserved genomic elements, which indicates their importance to vertebrate biology. Examination of these highly conserved events has led to new insights into the functions of AS-NMD and the role it can have in physiological circumstances.