Although cytoplasmic capping was characterized ten years ago many of the key mechanistic questions regarding its regulation remain unknown. This MIRA proposal outlines my last five years of progress (both as a postdoc and a new PI) towards better understanding how the cytoplasmic capping machinery recognizes its substrates. I present preliminary data that multiple sequence elements located at the 5’ ends (via 5’-truncated mRNAs), the 3’ ends (via alternative cleavage and polyadenylation), and the internal exonic sequences (via alternative splicing) may all contribute to RNA recognition by the cytoplasmic capping machinery. Further, I also present preliminary data consistent with the translation of 5’-truncated, yet cytoplasmically-capped mRNAs. Those data lend strong evidence to the hypothesis that cytoplasmic capping acts as an additional layer of post-transcriptional gene regulation. This proposal pursues cytoplasmic capping as a driver of gene regulation in endothelial cells. In particular we will assay the role(s) of cytoplasmic capping in the oxidative stress response.