Myocardial infarction, peripheral arterial disease, and stroke are highly morbid and mortal conditions [1] that are consequent to the progression of atherosclerotic plaque lesions in the intimal component of vascular wall. Atherosclerosis silently develops over decades of life from sub-endothelial fatty streaks deposition into established lesions compromising blood flow in the arterial vessel that may rupture causing an acute luminal occlusion and organ ischemia [2]. In spite of the higher prevalence reported in modern industrialized societies [1], atherosclerosis has impacted human health for centuries as evidenced by the recent documentation of lesions in ancient Egyptian mummies [3]. Clinical, pathologic, and experimental observations have fueled the current zeitgeist that atherosclerosis is a chronic inflammatory disease state. This central feature of atherosclerosis is under enormous investigative efforts to dissect the proand anti-inflammatory cellular and molecular mechanisms governing disease development [4]. A number of cellular pathways have been implicated in modulating this pathologic inflammatory process [5]. Studies utilizing high throughput technologies coupled with enormous advances in our understanding of the human genome have led to the discovery of many atheroregulatory candidates. Amongst the most exciting developments of the past decade has been the identification of a family of transcriptional regulators termed Kruppel-like Factors (KLFs) as athero-protective factors [6]. Indeed, studies from our group and others have demonstrated the key role of this family of transcription factors (KLFs) in governing cell activation and inflammatory responses in many cellular components of the vascular wall and plaque lesion. The nomenclature of KLFs came from the German word kruppel (for “cripple”), a protein first described in Drosophila [7]. Embryos with mutated kruppel had a lethal developmental defect in body patterning and a “crippling” appearance. In 1993, the first mammalian homolog to kruppel was identified in red blood cell lineage, therefore named erythroid Kruppel-like factor (EKLF/KLF-1)[8]. Over the last two decades, a total of 17 members were identified in mammalians constituting a large family of KLFs that broadly regulate numerous physiological and pathological processes in many cell types and organ systems [. 9], from fetal development to circadian regulation of cardiac repolarization [10, 11]. KLFs represent a subgroup of the zinc finger family of DNA-binding transcription factors, and they are distinguished by several features: i) three Cysteine2/Histidine2 containing zinc fingers located at the extreme C-terminus of the protein, ii) a highly conserved seven residue sequence between zinc fingers, TGEKP (Y/F) X, and iii) DNA-binding to specific sequences such as the “CACCC” sequence or the “GT box”[12–14]. The highly divergent non-DNA-binding regions mediate protein-protein interactions, and modulate transactivation and transrepression. In this review we summarize the emerging role of certain members of the KLF transcription factors in the endothelial, smooth muscle, and immune cells biology with a focus on inflammation and implications for atherosclerosis (summarized in Table 1).