The explosion in sequencing technologies has provided us with an instrument to describe mammalian transcriptomes at unprecedented depths. This has revealed that alternative splicing is used extensively not only to generate protein diversity, but also as a means to regulate gene expression post‐transcriptionally. Intron retention (IR) is overwhelmingly perceived as an aberrant splicing event with little or no functional consequence. However, recent work has now shown that IR is used to regulate a specific differentiation event within the haematopoietic system by (...) coupling it to nonsense‐mediated mRNA decay (NMD). Here, we highlight how IR and, more broadly, alternative splicing coupled to NMD (AS‐NMD) can be used to regulate gene expression and how this is deregulated in disease. We suggest that the importance of AS‐NMD is not restricted to the haematopoietic system but that it plays a prominent role in other normal and aberrant biological settings. (shrink)