The steady-state levels of mRNAs depend upon their combined rates of synthesis and processing, transport from the nucleus to cytoplasm, and decay in the cytoplasm. In eukaryotic cells, the degradation of mRNA is an essential determinant in the regulation of gene expression, and it can be modulated in response to developmental, environmental, and metabolic signals. This level of regulation is particularly important for proteins that are active for a brief period, such as growth factors, transcription factors, and proteins that control cell cycle progression. The mechanisms by which mRNAs are degraded and the sequence elements within the mRNAs that affect their stability are the subject of this review. We will summarize the current state of knowledge regarding cis-acting elements in mRNA and trans-acting factors that contribute to mRNA regulation decay. We will then consider the mechanisms by which specific signaling proteins seem to contribute to a dynamic organization of the mRNA degradation machinery in response to physiological stimuli.