Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional regulatory mechanism in eukaryotic cells. NMD can recognize and degrade abnormal transcripts containing premature termination codons (PTC) to prevent the translation of C-terminal truncated proteins. Furthermore, NMD could degrade a subset of normal gene transcripts and thus fine-tune gene expression. NMD is essential for cell fate determination, stress response, as well as animal development. In this review, we briefly discussed the functional and molecular mechanisms of NMD pathway activation and inhibition in tumorigenesis, cancer progression and therapy. Current studies indicate that NMD factor mutations can lead to a variety of human tumors. Interestingly, inhibition of NMD factors can activate DNA damage response and inhibit the expression of oncogenic factors, thereby killing cancer cells. This review may provide new perspectives for the biological mechanism and therapeutic strategy of human tumors.