Nonsense-mediated mRNA decay (NMD) is both a quality control mechanism and a gene regulation pathway. It has been studied for more than 30 years, with an accumulation of many mechanistic details that have often led to debate and hence to different models of NMD activation, particularly in higher eukaryotes. Two models seem to be opposed; the first model requires the intervention of the exon junction complex (EJC) to recruit NMD factors downstream of the premature termination codon (PTC), whereas the second model involves an EJC-independent mechanism in which NMD factors concentrate in the 3′ untranslated regions (3'UTR) to initiate NMD in the presence of a PTC. In this review we describe both models, giving recent molecular details and providing experimental arguments supporting one or the other model. In the end, it is certainly possible to imagine that these two mechanisms co-exist, rather than viewing them as mutually exclusive.