During the last decade evidence has accumulated that modulation of mRNA stability plays a central role in cellular homeostasis, including cell differentiation, proliferation and adaptation to external stimuli. The functional relevance of posttranscriptional gene regulation is highlighted by many pathologies, wherein occurrence tightly correlates with a dysregulation in mRNA stability, including chronic inflammation, cardiovascular diseases and cancer. Most commonly, the cis-regulatory elements of mRNA decay are represented by the adenylate- and uridylate (AU)-rich elements (ARE) which are specifically bound by trans-acting RNA binding proteins, which finally determine whether mRNA decay is delayed or facilitated. Regulation of mRNA decay by RNA stabilizing and RNA destabilizing factors is furthermore controlled by different intrinsic and environmental stimuli. The modulation of mRNA binding proteins, therefore, illuminates a promising approach for the pharmacotherapy of those key pathologies mentioned above and characterized by a posttranscriptional dysregulation. Most promisingly, intracellular trafficking of many of the mRNA stability regulating factors is, in turn, regulated by some major signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade, the AMP-activated kinase (AMPK) and the protein kinase (PK) C (PKC) family. In this review, we present timely examples of genes regulated by mRNA stability with a special focus on signaling pathways involved in the ARE-dependent mRNA decay. A better understanding of these processes may form the basis for the development of novel therapeutics to treat major human diseases.