The post translation modification of serine or threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide -N-acetyl-glucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification. Protein O-GlcNAcylation is rapidly emerging as a key regulator of critical biological processes including nuclear transport, translation and transcription, signal transduction, cytoskeletal reorganization, proteasomal degradation and apoptosis. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance major hallmarks of diabetes mellitus and diabetes-related cardio vascular complications. Conversely, there is a growing body of data demonstrating that the acute activation of O-GlcNAc levels is an endogenous stress response designed to enhance cell survival. Reports on the effect of altered O-GlcNAc levels on the heart and cardiovascular system have been growing rapidly over the past few years and have implicated a role for O-GlcNAc in contributing to the adverse effects of diabetes on cardiovascular function as well as mediating the response to ischemic injury. Here we summarize our current understanding of protein O-GlcNAcylation and its effect on the regulation of cardiovascular function. We examine the pathways regulating protein O-GlcNAcylation and discuss in more detail our current understanding of the role of O-GlcNAc in mediating both adverse effects of diabetes as well as its role in mediating cellular protective mechanisms in the cardiovascular system. In addition we also explore the parallels between O-GlcNAc signaling and redox signaling as an alternative paradigm for understanding the role of O-GlcNAcylation in regulating cell function.