Transcription factors play an important role in the pathophysiology of many neurological disorders, including stroke. In the past three decades, an increasing number of transcription factors and their related gene signaling networks have been identified, and have become a research focus in the stroke field. Krüppel-like factors (KLFs) are members of the zinc finger family of transcription factors with diverse regulatory functions in cell growth, differentiation, proliferation, migration, apoptosis, metabolism, and inflammation. KLFs are also abundantly expressed in the brain where they serve as critical regulators of neuronal development and regeneration to maintain normal brain function. Dysregulation of KLFs has been linked to various neurological disorders. Recently, there is emerging evidence that suggests KLFs have an important role in the pathogenesis of stroke and provide endogenous vaso-or neuro-protection in the brain's response to ischemic stimuli. In this review, we summarize the basic knowledge and advancement of these transcriptional mediators in the central nervous system, highlighting the novel roles of KLFs in stroke.