Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance pathway that cells use to ensure the quality of transcripts and to fine-tune transcript abundance. The role of NMD in cancer development is complex. In some cases, tumors have exploited NMD to downregulate gene expression by apparently selecting for mutations causing destruction of key tumor-suppressor mRNAs. In other cases, tumors adjust NMD activity to adapt to their microenvironment. Understanding how particular tumors exploit NMD for their benefit may augment the development of new therapeutic interventions.