Nonsense-mediated mRNA decay (NMD) is a highly conserved pathway that was originally identified as a RNA surveillance mechanism that degrades aberrant mRNAs harboring premature termination (nonsense) codons. Recently, it was discovered that NMD also regulates normal gene expression. Genome-wide studies showed that ablation of NMD alters the expression of ∼10% of transcripts in a wide variety of eukaryotes. In general, NMD specifically targets normal transcripts that harbor a stop codon in a premature context. The finding that NMD regulates normal gene expression raises the possibility that NMD itself is subject to regulation. Indeed, recent studies have shown that NMD efficiency varies in different cell types and tissues. NMD is also subject to developmental control in both higher and lower eukaryotic species. Molecular mechanisms have been defined-including those involving microRNAs and other RNA decay pathways-that regulate the magnitude of NMD in some developmental settings. This developmental regulation of NMD appears to have physiological roles, at least in some model systems. In addition to mechanisms that modulate the efficiency of NMD, mechanisms have recently been identified that serve the opposite purpose: to maintain the efficiency of NMD in the face of insults. This 'buffering' is achieved by feedback networks that serve to regulate the stability of NMD factors. The discovery of NMD homeostasis and NMD regulatory mechanisms has important implications for how NMD acts in biological processes and how its magnitude could potentially be manipulated for clinical benefit.