Krüppel-like factor 4(KLF4) is a zinc-finger transcription factor that plays a key role in cellular differentiation and proliferation during normal development and in various diseases, such as cancer. The results of recent studies have revealed that KLF4 is expressed in multiple vascular cell types, including phenotypically modulated smooth muscle cells(SMCs), endothelial cells and monocytes/macrophages and contributes to the progression of vascular diseases by activating or repressing the transcription of multiple genes via its associations with a variety of partner proteins. For example, KLF4 decreases the expression of markers of SMC differentiation by interacting with serum response factor, ELK1 and histone deacetylases. KLF4 also suppresses SMC proliferation by associating with p53. In addition, KLF4 enhances arterial medial calcification in concert with RUNX2. Furthermore, endothelial KLF4 represses arterial inflammation by binding to nuclear factor-κB. This article summarizes the role of KLF4 in vascular disease with a particular focus on in vivo studies and reviews recent progress in our understanding of the regulatory mechanisms involved in KLF4- mediated gene transcription.